A car bomb killed more than 50 people and wounded 200 in central Damascus when it blew up on a busy highway close to ruling Baath Party offices and the Russian Embassy.
Syrian television showed charred and bloodied bodies strewn across the street after the blast.
It was described as a suicide bombing by "terrorists" battling President Bashar al-Assad.
Syrian television said 53 people were killed in the blast.
Rebels who control districts to the south and east of Damascus have attacked Assad's power base for nearly a month and struck with devastating bombs over the last year.
The al Qaeda-linked rebel group Jabhat al-Nusra, which claimed responsibility for several of those bombs, says it carried out 17 attacks around Damascus in the first half of February, including at least seven bombings.
Activists said most of the victims of today's attack in the city's Mazraa district were civilians, including children, possibly from a school behind the Baath building.
Opposition activists reported further explosions elsewhere in the city after the explosion, which struck shortly before 11am.
One resident in the heart of the capital heard three or four projectiles whistling through the sky, followed by explosions. At least one of them landed in a public garden in the Abu Rummaneh district, she said, but no one was hurt.
Earlier, the opposition Syrian National Coalition said it is willing to negotiate a peace deal to end the country's civil war.
But in a communiqué issued for an opposition meeting, it said President Bashar al-Assad cannot be a party to any settlement.
The communiqué, seen by Reuters, omitted a direct demand for Mr Assad's removal, in a softening of tone from past positions that insisted the president must go before there could be any talks.
It will be debated at a meeting of the opposition alliance's leadership starting in Cairo later today.
The SNC said Mr Assad and his cohorts must be held accountable for bloodshed and that any peace deal must be under the auspices of the US and Russia.
"Bashar al-Assad and the military and security apparatus commands are responsible for the decisions that have led the country to what it is now are outside the political process and are not part of any political solution in Syria," it said.
"They have to be held accountable for the crimes they have committed."
The initiative comes from coalition president Moaz Alkhatib, a cleric from Damascus, who played a role in the peaceful protest movement against Mr Assad at the beginning of the uprising almost two years ago.
Russia and Arab League offer to engage with Syria
Russia and the Arab League have proposed brokering direct talks in an attempt to end the civil war in Syria.
Russian Foreign Minister Sergei Lavrov said the violence was "a road to mutual destruction".
Russia still keeps close ties with the regime of President Assad, and has so far refused to halt military cooperation with Syria.
The proposal received a cool reception from the opposition.