A Libyan official accompanying journalists at Qaddafi's compound said 45 people were wounded, 15 seriously, in the bombing. He added that he did not know whether there were victims under the rubble.
"It was an attempt to assassinate Colonel Qaddafi," he affirmed.
Seif Al-Islam, Qaddafi's son, described the bombing as "cowardly."
"This cowardly attack on Moamer Qaddafi's office may frighten or terrorize children but we will not abandon the battle and we are not afraid," he said, claiming that NATO's battle was "lost in advance."
NATO warplanes had already late Friday targeted the Bab Al-Aziziya district, where the presidential compound is located.
"Have you seen all these people who are at Bab Al-Aziziya despite the raids?" Seif Al-Islam asked. "How are you going to vanquish these people?"
At around 3:00 am (0100 GMT) smoke was still rising from part of the building that was hit, watched by dozens of people shouting slogans praising the Guide.
A meeting room facing Qaddafi's office was badly damaged by the blast.
African leaders had met these with Qaddafi two weeks ago to propose a peace plan that was accepted by the regime, but turned down by the rebels.
The international coalition had already destroyed a building in the presidential compound, calling it a command centre.
Heavy explosions had shaken the centre of Tripoli shortly after midnight Monday (2210 GMT Sunday) as warplanes overflew the Libyan capital. The blasts, the strongest to have hit the city so far, shook the hotel in which foreign correspondents here are staying not far from downtown.
The explosions hit several districts of Tripoli, which has been the target since Friday of intense NATO raids.
Libyan state television transmissions were briefly cut off right after the explosions, before resuming a few minutes later.
The official state news agency JANA quoted a military source as saying that "several military and civilian sites in the city of Tripoli were the targets of raids by the crusader colonialist aggressor (NATO) which caused human and structural damage."
An international coalition intervened in Libya on March 19 under a UN mandate to end the bloody suppression of a revolt that started in mid-February against the Qaddafi regime, which has been in power for 41 years.
The North Atlantic Treaty Organisation took over command of the military intervention on March 31.
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