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.
About 40 people were also reported to have been injured.
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, SANA, 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 aim of this cowardly and desperate terrorist attack is to raise the morale of the defeated terrorist groups following the great victories that our brave army has accomplished in several areas,” Prime Minister Wael al-Halqi told SANA.
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.
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 said 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.