There was immediate evidence of sharp differences, as U.S. Secretary of State John Kerry insisted that President Bashar al-Assad must step down, while Russian Foreign Minister Sergei Lavrov cautioned against outsiders meddling in Syria's affairs.
United Nations Secretary-General Ban Ki-moon opened what will be a day of speeches at Montreux on Lake Geneva from more than 40 delegations, including the opposing sides in Syria, by painting a bleak picture of the suffering of millions and of abuses of human rights by all the warring parties.
"Syrians must start talking to each other again," Ban said, urging both sides to reach a comprehensive settlement based on the U.N. Geneva Communique, under which world powers called in 2012 for a transitional government to oversee change in Syria.
"There is no alternative to ending the violence ... I appeal to all of you to show greater vision for humanity."
Calling the challenges ahead great but not insurmountable, he called for immediate access for aid to areas under siege.
Western powers and Russia have sought to set aside their own sharp differences over whether Assad must be forced to make way for an interim administration and have backed the conference as a way to stop the spread of communal and sectarian violence spreading across the region.
The conference, which Ban hopes will be followed by further talks in Geneva, has raised no great expectations, particularly among Islamist rebels on Syria's frontlines who have branded Western-backed opposition leaders as traitors for even agreeing to be in the same room as Assad's delegates.
Underlining the seemingly intractable positions, Syrian Foreign Minister Walid al-Moualem said on Tuesday that Assad's position was non-negotiable. "The subject of the president and the regime is a red line for us and the Syrian people and will not be touched," he was quoted as saying in Syrian media.
Lavrov, co-sponsor of the conference with Kerry, repeated Moscow's opposition to "outside players" meddling in Syria's affairs but he also said Iran - Assad's main foreign backer - should have a say.
Kerry, in his brief speech to the floor, said negotiations would be "tough and complicated" but insisted there was "no way" Assad could stay on with a transitional government.
"One man can no longer hold an entire nation or region hostage," Kerry said, while also adding there would be no room in government for "terrorists" among the rebel forces.
Assad backer Iran was not present. A last-minute invitation from Ban to attend was revoked on Monday after the Syrian opposition threatened to boycott the talks, since Iran shares Assad's view that he should not lose power.
Iranian President Hasan Rouhani said that made it unlikely the conference could succeed: "Because of the lack of influential players in the meeting, I doubt about the Geneva 2 meeting's success in fighting against terrorism ... and its ability to resolve the Syria crisis," Rouhani said.
"The Geneva 2 meeting has already failed without it even being started," he was quoted as saying by IRNA news agency - though he added he would be pleased if it did help bring peace.
As speeches began in Montreux, the war went on in Syria.
The Syrian Observatory for Human Rights monitoring group reported clashes and air strikes around the country. Around Damascus, government artillery hit villages and rebels clashes with the army in the neighbourhood of Jobar on the northeast fringe of the capital, it said. Activists also reported clashes and in the central city of Hama, the southern province of Deraa - where the revolt began - and the northern city of Aleppo.
French Foreign Minister Laurent Fabius said on arrival: "The real conference begins in two days. If it fails it will be a real crisis."
Suhair Attassi, a member of the opposition National Coalition, said in Montreux that Moualem's refusal to accept Assad should go meant it would be up to his Russian ally to press him to accept the international demand for a transition.
"Now there is the responsibility on Russia to put pressure on Assad," he said. "The transition for us is the essential point. We aren't here just to talk humanitarian aid. We need a democratic transition."
The release on the eve of the talks of thousands of photographs apparently showing prisoners tortured and killed by the government reinforced opposition demands that Assad must quit and face a war crimes trial. The president, who succeeded his father 14 years ago, insists he can win re-election and wants to talk about fighting "terrorism."
Assad has been protected by Russia, his main arms supplier, which dislikes Western attempts to overthrow incumbent leaders.
But Washington and Moscow share alarm at the spread of the violence that has already killed more than 130,000 Syrians. Having set aside their differences last year to co-sponsor the talks that are finally getting under way, Russia and the United States profess an urgent common goal of halting the bloodshed.
"It is hard to have expectations at the back of all this," said a source at the talks who has advised the opposition. "But Moscow and Washington are genuine on ending the conflict. They are sincere and this meeting is not for show."
Assad's representatives may highlight the threat to the West and its Arab allies from al Qaeda and other militants fighting his forces. But Western leaders say they fully back opposition demands that Assad step down, something they say was the conclusion of the U.N. conference in Geneva 18 months ago.
Russia endorsed that communique but has disagreed with Western powers which say that, by calling for a transitional government in Damascus, the meeting known as Geneva 1 made Assad's removal a condition for a peace settlement.
Neither side in Syria has either appeared able to complete a victory. Though much divides the rebels, who have been fighting among themselves, they are united in wanting Assad out. So reaching a settlement that satisfies both sides seems a distant prospect.
Discontent stretches back to the rule since 1970 of Assad's father, who took power in a military coup, but it boiled over in March 2011 as Syria's drought-hit economy struggled and the Arab Spring uprisings in Tunisia and Egypt inspired protests.
When those were crushed, the revolt became a war that has taken on an increasingly sectarian complexion, setting majority Sunnis against Assad's Alawite community, an offshoot of Shi'ite Islam. It has also drawn in rival powers with Saudi Arabia and Qatar backing the rebels and Iran standing by Assad.
Al Qaeda-linked militants and other Islamists have emerged as the most powerful forces on the rebel side, dampening Western appetite for direct intervention. Iran and its Lebanese Shi'ite ally Hezbollah have helped Assad. And violence has spread, notably to neighbouring Iraq and Lebanon.
For all the low expectations on Lake Geneva, millions of Syrians in refugee camps hope something will change. "Let them please find a solution for this problem," Mohammed from Homs said at a U.N. centre in Lebanon. "Let us go home."
* Day of speeches opens with U.N., U.S., Russian remarks
* UN's Ban calls for immediate humanitarian access
* Russia's Lavrov says outsiders must not meddle in Syria
* U.S. secretary Kerry said Assad can have no role in transition