BBC-Syria's defence minister and his deputy, President Assad's brother-in-law, have died in a suicide bombing at security headquarters in Damascus, state TV says.
Daoud Rajiha and Assef Shawkat were attending a meeting of senior officials at the time.
The national security chief and interior minister are said to be critically hurt.
The attack comes amid claims of a major rebel offensive on the city.
The rebel Free Syrian Army (FSA) and a jihadist group calling itself Lord of the Martyrs Brigade both said they were behind the bombing.
Hours after the attack, several explosions were reported close to the base of an army division responsible for guarding the presidential palace. However Syria's information minister denied that they had taken place.
The army's fourth division, commanded by the president's brother, Maher al-Assad, is considered one of the army's best-equipped.
No footage has emerged of the attack and the BBC's Lina Sinjab in Damascus says there is no sign of extra security outside the security headquarters.
But a statement by the armed forces read out on TV said Syria was "more determined than ever" to fight terrorism and wipe out "criminal gangs".
Whoever thinks that killing top commanders "can twist Syria's arm... is delusional", it said.
But the BBC's Jim Muir, in neighbouring Lebanon, says that the rebels now clearly believe that victory is within sight, and the deaths will give them even greater heart.
Security sources say the suspected bomber worked as a bodyguard for members of President Bashar al-Assad's inner circle.
Gen Rajiha had been defence minister for less than a year, serving previously as chief of staff, and was on a US blacklist for his role in the suppression of dissent.
He was believed to be an Orthodox Christian - a rarity in the Alawite-dominated Syrian military and government.
Gen Shawkat was considered a top security chief and a member of the inner circle of the regime. He is married to Mr Assad's sister Bushra.
The defence minister has been replaced by Gen Fahd Jassim al-Furayj, state TV reports, chief of staff of the armed forces.
The area around the national security building, in Rawda district, has been sealed off.
Witnesses at the site of the bombing said journalists were banned from approaching.
"The terrorist explosion which targeted the national security building in Damascus occurred during a meeting of ministers and a number of heads of [security] agencies," the TV said.
The reports say that Hisham Ikhtiar, director the National Security Bureau, and Interior Minister Mohammad Ibrahim al-Shaar, were among those injured in the attack.
Earlier, activists reported more clashes during the night in several areas around the south-west of Damascus.
They said the government had brought more troops and armour into some districts, and that several people had been killed in clashes and bombardments.
A rebel spokeswoman, Susan Ahmad, told the BBC the entrances to Damascus were closed on Wednesday morning.
"Now tanks are storming into al-Qaboun [district], shelling everything, shelling residential houses, shooting every moving thing and they are trying to arrest people and kill.
"People are trying to run away and get out of al-Qaboun."
Activists have also posted on the internet pictures of what they say is a barracks on the heights overlooking the city engulfed in flames.
They believed it had been hit by fire from Free Syrian Army (FSA) rebels, and said the barracks was involved in providing security for the presidential palace complex below.
State media said security forces fought off attacks by small groups of armed terrorists in the city.
But the TV carried night-time footage of troops deployed in the Midan quarter, in some very tense and deserted streets.
The rebels have declared a final battle for the capital, calling it Operation Damascus Volcano, and have been fighting troops in several parts of Damascus for the past three days.
The fighting reached central areas on Tuesday, with gunfire and plumes of smoke reported in a street near parliament.
The Free Syrian Army said the operation was well planned, and they had sent hundreds of fighters to the capital last week to be in place for the assault.
The rebels and the government often publish contradictory accounts of the same incidents.
Western journalists are under heavy restrictions in Syria, making it difficult to verify the claims of either side.
Hours before the UN Security Council was due to vote on a new round of sanctions against Syria, Russian Foreign Minister Sergei Lavrov warned that the battle for the country's capital was under way.
UN chiefs, who have until Friday to renew the mandate for observers in Syria, have been trying to persuade China and Russia to agree tougher measures on Damascus.
Speaking at a news conference with his UK counterpart in Washington, US Defence Secretary Leon Panetta said the situation appeared to be spiralling rapidly out of control.
Opposition groups say as many as 16,000 people have died in Syria since protests against President Assad began in March last year.