Syrian Defence Minister Daoud Rajha and his deputy Assef Shawkat - the brother-in-law of President Bashar al-Assad - have been killed in what state television called a "terrorist explosion" at a national security building in Damascus.
Opposition activists said Interior Minister Mohammed Ibrahim al-Shaar was among those seriously wounded in the bombing.
State-run TV said Shaar was in stable condition.
The activists claimed that the attack had been carried out by a suicide bomber from the rebel Free Syrian Army.
State television reported that the bombing took place as government ministers and a number of security officials were meeting at the building in the district of Rawda, and that many of them were seriously wounded.
Security officials said that several other participants in the cabinet meeting were taken to al-Shami hospital in the capital for treatment.
Rajha was the most senior Christian government official in Syria, appointed by Assad to the defence minister post last year.
His death will resonate with Syria's minority Christian population, who make up about 10 per cent of the country's population and has generally stood by the regime.
General Shawkat was one of Syria's top security officials and married to Assad's elder sister, Bushra.
The attack came amid reports of clashes in Damascus between forces loyal to Assad and opposition rebels for the fourth consecutive day.
The state-run news agency SANA reported that Wednesday's blast was aimed at the national security building, a headquarters for one of Syria's intelligence branches and less than 500 metres from the US embassy.
Police had cordoned off the area, and journalists were banned from approaching the site.
A divided United Nations Security Council was set to vote later on a contested draft resolution threatening sanctions against Assad's government.
Russia opposes demands by the United States and European powers that the resolution should threaten sanctions under Chapter VII of the UN charter, which could allow military action.
Russia and China, Syria's main allies, have in the past vetoed two UN resolutions condemning Assad for his crackdown on the 17-month revolt.