Security forces are said to have killed at least 32 protesters in the Syrian capital Damascus, Idlib province and Deraa.
Police opened fire with live ammunition as hundreds of thousands of demonstrators poured into the country's streets.
The people are demanding the removal of President Bashar al-Assad in what appears to be the biggest demonstrations since the revolt against his 11-year rule started in March.
Some 20,000 people turned out in the Damascus neighbourhood of Qabun, where two people were killed, and three others were killed in Idlib, said Abdel Karim Rihawi, of the Syrian League for the Defence of Human Rights.
Another 11 people were shot elsewhere in the capital city, including a child.
In the central city of Homs, 15 people were wounded when security forces fired on them.
Syrians had been urged to demonstrate after Friday prayers to demand the release of those people imprisoned in a crackdown on democracy protests, four months after they erupted.
Activists issued an appeal for protests to mark a day of 'freedom for the hostages' on The Syrian Revolution 2011 page of Facebook, which has been a driving force behind the demonstrations.
The Facebook appeal called for nationwide demonstrations 'for the freedom of prisoners, for the dignity of free men'.
Syrians have adopted Fridays, when they are allowed to gather for the main weekly Muslim prayers, as their main outlet for dissent.
Security agents used live rounds to disperse protesters in the Qabun and Barzeh areas of the Damascus, while more demonstrators infiltrated the Madaya, Harasta and Saqba regions, Mr Rihawi said.
The official Sana news agency said 'armed men fired on security forces and citizens in the areas of Qabun and Rukn Eddin in Damascus'.
Rami Abdel Rahman of the Syrian Observatory for Human Rights said about 350,000 people turned out in the eastern city of Deir Ezzor, while 150,000 others in Hama protested against President Bashar al-Assad.
Following the latest violence in Syria an European diplomat has said the EU is ready to increase pressure on the country through sanctions.
A text read out by the diplomat said 'the EU will pursue and carry forward its current policy, including through sanctions targeting those responsible for or associated with the violent repression.'
The stance is expected to be formally adopted by European foreign ministers on Monday.