At least 45 people have been killed in three blasts near the Shia shrine of Sayyida Zeinab, south of the Syrian capital Damascus, state media say.
Scores of people were also reported to have been wounded.
The shrine, which is highly revered by Shia Muslims, has been targeted before, most recently in February last year.
The attacks came as delegates from the Syrian government and opposition groups gathered in Geneva for tentative UN-sponsored peace talks.
The main opposition group backed down from its threat to boycott the talks. but says the Syrian government must meet key demands if negotiations are to start.
Syrian state media say the blasts near Sayyida Zeinab were caused by a car bomb and two suicide bombers.
TV footage showed burning buildings and destroyed cars.
The shrine contains the grave of one of the Prophet Muhammad’s grand-daughters. It continues to draw many Shia pilgrims, despite the civil war.
At the scene: Rami Ruhayem, BBC News, south-eastern Damascus
The destruction is huge. The building in front of me on Koua Soudan Street is charred black in the middle. I’m told that there is a military headquarters on the ground floor and families also lived in the five-storey building.
There is a fruit stall with blackened oranges all over the floor.
I can also see a large number of charred vehicles, including a bus in the middle of the street which is almost completely destroyed and overturned. The smoke still rising from one of the cars on the side of the street.
BBC Arab affairs editor Sebastian Usher says Shia fighters from around the region have joined the conflict in Syria on the grounds that they wish to protect the shrine from the civil war.
The Lebanese Shia movement Hezbollah has cited it as a key reason that it chose to fight on the side of President Bashar al-Assad, he adds.
More than 250,000 people have died and 11 million have fled their homes in almost five years of civil war in Syria. The violence has also been the biggest driver behind Europe’s migration crisis.
In Geneva, the delegation of the Saudi-backed opposition group the High Negotiations Committee (HNC) met UN envoy Staffan de Mistura on Sunday.
Mr Mistura described the talks as “a good start” and told the BBC he was “optimistic”. He said the HNC would give more details later.
Earlier, HNC spokesman Salim Muslet had said that they stood by their demand for an end to air strikes and blockades before they would negotiate with the Syrian government.
The HNC finally agreed late on Friday that it would travel to Geneva – hours after the Syrian government delegation had arrived and held preliminary talks with Mr Mistura.
The so-called proximity talks are expected to last six months, with delegations sitting in separate rooms and UN officials shuttling between them.
UN chief Ban Ki-moon called on all sides to put the interests of Syrians above their own.
“Children and women in particular have borne the brunt of this fighting and it is time now to see the end of the fighting and other human rights abuses that have dominated the war,” he said.