Syrian Prime Minister Riad Hijab has defected from President Bashar al-Assad's government to join "the revolution", his spokesman says.
Mr Hijab was appointed less than two months ago and his departure is the highest-profile defection since the uprising began in March 2011.
State-run TV said he had been sacked.
Riad Hijab, who is said to have fled with his family, is a Sunni Muslim from the Deir al-Zour area of eastern Syria which has been caught up in the revolt.
Early reports said Mr Hijab had defected to Jordan, but Jordanian state TV later denied this. By Monday afternoon, Mr Hijab's whereabouts were still unknown.
'Freedom and dignity'
Earlier, his spokesman Mohammed el-Etri told al-Jazeera TV that he was in "a safe location".
"I address you today at this grave hour where the country is living under the brunt of genocide and barbarian brutal killing against unarmed people who are simply demanding freedom and a dignified life," ran Mr Hijab's statement read by his spokesman.
"Today I declare... that I have defected from the terrorist, murderous regime and [am] joining the holy revolution. And I declare that from today I am a soldier of this holy revolution."
Mr el-Etri later told the BBC that the Syrian regime was "now in its last throes" and that it had been dealt "a fatal blow" by Mr Hijab's defection.
"This defection was not a matter of days or weeks, it was in the pipeline for two continuous months through a trusted cell close to the prime minister made up of rebels and aides," Mr el-Etri said.
He said Mr Hijab would work to "rebuild a Syria of the future, a Syria without Bashar al-Assad".
Mr Hijab is the first Syrian cabinet minister to defect.
The BBC's Jim Muir in neighbouring Lebanon says the defection is a stunning blow to President Assad and a clear sign of the stresses building up within the regime.
White House spokesman Jay Carney said the defection was a sign that President Assad's grip on power was loosening.
"The momentum is with the opposition and with the Syrian people," he told reporters.
Unconfirmed reports suggested that two other cabinet ministers had also deserted and there were claims that a third, Finance Minister Mohammad Jalilati, had been arrested while trying to flee.
But Syrian state TV said Mr Jalilati was still in his office working as usual, and it broadcast what it said was a phone interview with him denying reports that he had been detained.
Last month, Syria's ambassador to Iraq, Nawaf Fares, deserted to the opposition. Like Mr Hijab, he was also from Deir al-Zour. Brig Gen Manaf Tlas, who was considered close to President Assad, defected in July.
Thirty other generals have crossed into Turkey so far and Turkish news agency Anatolia reported on Monday that another general had fled with five high-ranking officers and more than 30 soldiers.
Our correspondent said Mr Hijab had been regarded as a Baath party loyalist who was appointed following May general elections which were part of President Assad's reform process.
Syrian state TV said Mr Hijab's deputy, Omar Ghalawanji, would replace him as PM.
'Aleppo facing carnage'
Hours earlier, state TV said a bomb had gone off at the Syrian state TV and radio building in Damascus, wounding three people.
A BBC Arabic reporter in the capital said the explosion in Umawiyeen Square had "ripped the floor" but transmission was unaffected.
Pro-government forces have regained control of areas of Damascus seized by rebels in recent weeks but the rebels are continuing to hold out in the second city, Aleppo.
Opposition activists reported an intense bombardment of parts of Aleppo on Monday as 20,000 troops surround the northern city.
A spokeswoman for the exiled opposition Syrian National Council (SNC) told French radio station Europe1 that Aleppo was undoubtedly facing "carnage".
Meanwhile, Iran has strongly denied that 48 Iranians seized by Syrian rebels at the weekend include members of Iran's Revolutionary Guards.
Rebels posted an online video of the Iranians on Sunday, saying they had been seized from a bus in Damascus the day before.
The rebels alleged they were on a reconnaissance mission in the capital.
Tehran, a key ally of President Assad, says they were visiting a renowned Shia pilgrimage site and has appealed to Turkey and Qatar to help secure their release. A rebel commander said their documents were still being checked.