Amman: At least 60 people were killed, including 25 fighters, and dozens wounded on Sunday by a car bomb and two suicide bombers in a district of Damascus where shrine is located, a monitor said.
IS claimed responsibility for the attacks, according to Amaq, a news agency that supports the group. It said two operations "hit the most important stronghold of militias in Damascus".
The Syrian Observatory for Human Rights said the casualties were expected to rise from the suicide attacks in Sayeda Zeinaba, a district of southern Damascus where militias have a strong presence.
Rami Abdulrahman, head of the British-based Observatory, said the suicide bombers had targeted a military bus carrying militias who were changing guard there.
The explosions occurred as representatives of Syria's government and its divided opposition began convening in Geneva for the first UN-mediated peace talks in two years.
Syrian Ambassador Ibrahim Jaafari, head of the government delegation at Geneva, said the blasts in Damascus just confirmed the link between what the government says are a foreign funded "opposition" and terrorism.
State television showed footage of burning buildings and wrecked cars in the neighbourhood.
Syrian state news agency SANA, quoting an interior ministry source, said a group of militants had detonated a car bomb near a public transport garage in the neighborhood's Koua Sudan area.
Two suicide bombers then blew themselves up nearby as people were being rescued. The authorities put the dead at 45 people.
"Bodies were still being pulled from the wreckage," a witness told state news channel Ikhbariyah.
The heavily populated area in the south of the city is a site of pilgrimage.
Syrian Prime Minister Wael Al Halaki was quoted as saying the attacks were prompted by "terror groups" who sought to "raise their morale after a string of defeats" by the army.
The United Nations has said it is aiming for six months of talks, first seeking a ceasefire and later working toward a political settlement for Syria. The nearly five-year conflict has killed more than 250,000 people, driven more than 10 million from their homes and drawn in global powers.
The Sayeda Zeinab shrine area witnessed heavy clashes in the first few years of the war but has since been secured by the Syrian army and militias, which has set up protective roadblocks around it.
Rebels says the area is the first destination of thousands of militias before heading to fight in battlefields across the country.
Militias from the region have played a crucial role in covering the shortfall in manpower faced by Syrian President Assad's overstretched army during nearly five years of conflict.