The last session in February may have produced a "clear agenda", according to UN Syria envoy Staffan de Mistura, but the regime and rebels oppose each other on all its points.
The talks aim to find a solution to end a six-year conflict that has killed more than 320,000 people and displaced millions since it started in 2011 with protests against President Bashar al-Assad's regime.
This round's agenda includes the issues of governance -- a political transition -- the constitution and elections, as well as counter-terrorism at the request of Damascus.
The United Nations said on Tuesday that all sides who had already attended the last round of negotiations in February had confirmed their attendance for this week.
"These will be 'proxy talks', direct talks have been excluded," a Western source close to the negotiations told AFP.
De Mistura, who wants the three main topics to be discussed "in parallel", will be in charge of mediating, the source said.
But his task will be tough as, according to analysts and diplomats, neither the opposition nor the regime is likely to make concessions.
The opposition has since 2011 called for Assad to step down, but the president refuses.
And the Damascus regime, which describes the rebels as "terrorists", wants the issue of "counter-terrorism" to be given priority at the negotiations.
- 'Tough' talks -
"There's no hope in my view," Syria specialist Thomas Pierret said.
"The regime continues to gain ground... There's no reason for it to make the slightest concession."
Since Russia's military intervention in support of Assad in 2015, the regime has gained the upper hand, claiming a series of victories against the rebels and jihadists.
Noah Bonsey, an analyst with the International Crisis Group, said this made Damascus unlikely to make concessions.
"The regime, unwilling to compromise when it was losing ground militarily, is even less likely to do so now that it has momentum," he said.
Regime troops retook the whole of Syria's second city Aleppo in December, in a major blow to the rebels and in what analysts described as a "turning point" in the war.
"These negotiations are tough," a French diplomatic source said.
"The opposition is fractured and over the past months we have seen a slow deterioration of the balance of power to its disadvantage."
Both sides accuse each other of a lack of commitment to finding a solution.
Yehya Aridi, one of the advisers to the High Negotiations Committee (HNC) main opposition group, said the regime was being "stubborn".
"There's little hope due to the stubbornness of the other side, which doesn't really want to find a solution," he said.
He accused the regime of using a strategy of years of bombing and siege to obtain the surrender and "submission" of fighters in rebel-held areas.
But Bassam Abu Abdallah, an analyst who is close to the regime, said the regional allies of the opposition were the ones hindering the peace talks.
- No US involvement -
"For the first time there is a clear agenda. But each time there's any political progress, fighters linked to regional powers carry out new attacks," the head of the Damascus Centre for Strategic Studies said.
He was referring to rebels and allied jihadists pressing an attack since Sunday in east Damascus in one of the most violent offensives on the capital in two years.
Delegations from both sides are due to arrive in Switzerland on Wednesday, to be welcomed by de Mistura's deputy, Ramzy Ezzeldin Ramzy.
The Syria envoy is currently visiting key powers shaping the conflict -- including Saudi Arabia, Russia and Turkey -- before returning to Geneva to lead the talks.
Moscow and Ankara brokered a fragile Syria ceasefire in force since December 30 last year.
During the last round, Russian pressure on the Syrian regime seemed to have paid off when Damascus for the first time publicly announced it was prepared to discuss de Mistura's three key talking points of governance, constitution and elections.
But on the opposition side, the new administration of US President Donald Trump has so far not given any sign of being involved in seeking a solution to the Syrian conflict.
"The vision of the United States is not yet clear... and a solution in Syria will only happen on the back of a deal between Russia and the US," said Abu Abdallah of the Damascus Centre.