The talks will for the first time gather all the major foreign players in the war -- the United States, Russia, Iran, Saudi Arabia and Turkey -- in the same room.
But while Tehran's inclusion in the negotiations is seen as a crucial shift, the path out of war remains strewn with obstacles.
What will Friday's talks focus on?
A key issue is the future of Syria's embattled President Bashar al-Assad.
The US and its Arab and Turkish allies have long been at odds with Assad's backers Russia and Iran over if and when the Syrian strongman should resign.
Ahead of the talks, US officials expressed a cautious hope that the players will agree the outline of a transition that would see Assad step aside in favour of an interim unity regime.
"Clearly, the most important discussion is about what a transitional government looks like, how is it composed (and) organised," said John Kirby, the spokesman for US Secretary of State John Kerry.
Europe's migrant crisis has helped convince Western leaders that Assad "was the lesser of two evils", according to Karim Bitar of the Institute for International and Strategic Relations in Paris.
"Most Westerners have adopted a more realistic stance on Syria and sort of accepted the idea that Assad will remain at the helm for a transition period."
Is Iran's involvement a game changer?
Tehran and Washington, foes since Iran's Islamic revolution, have no diplomatic ties and Iran's presence in Vienna is seen by experts as a sign of progress.
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The fact that Iran's other enemy Saudia Arabia has also accepted Tehran's presence is equally "significant", said Bitar.
"It's unlikely that (the talks) will lead to a definitive accord but in any case it's the start of a new phase," Bitar told AFP.
A senior European diplomat called Iran's inclusion "essential".
"Leave Tehran out of it and they will remain troublemakers," the diplomat told AFP on condition of anonymity.
"The only solution for finding an end to the Syrian crisis is to put as many parties as possible around the table. In doing that, the opening of negotiations -- even if it's just a start -- is a good thing."
What are potential stumbling blocks?
Despite their willingness to join the negotiating table, major differences remain between the participants.
One hurdle to a breakthrough could come from Riyadh and Istanbul demanding a quick exit for Assad -- a move likely to be opposed by Moscow and Tehran.
"The question now is whether the Russians and Iranians will propose a very long transition period that could stretch on forever," said Bitar.
French Foreign Minister Laurent Fabius has already warned that "several rounds of talks (will) certainly be necessary" before any real progress can be made.
But at least major players have opened a proper dialogue, said the senior European diplomat who asked not to be named.
"It was crucial to create a space for discussions, to find a format to lead the negotiations, as was the case for the nuclear talks with Iran. It took years but eventually worked," the diplomatic source added.