The latest bloodletting in the Syria crisis came as the UN Security Council remained divided over punitive measures against President Bashar al-Assad's regime, with Russia and China boycotting a key session aimed at endorsing fresh sanctions, including a total arms embargo.
On the political front, the ruler of the energy-rich state of Qatar, Sheikh Hamad bin Khalifa al-Thani, piled pressure on Syria during a visit to key Damascus' ally Iran, saying the use of force is "fruitless."
The Syrian Revolution 2011 Facebook group, one of the drivers of the protests since March in defiance of deadly government crackdowns, had called the rallies under the banner of "Friday of patience and determination." "We will not rest until the fall of the regime," said the message.
Rights activists said tens of thousands of people took to the streets after the midday Friday prayers, defying a deadly government crackdowns on dissent that the UN says has killed more than 2,200 people since mid-March.
The protesters chanted: "Bashar we don't love you, even if you turn night into day," and "We are men of freedom."
The Britain-based Syrian Observatory for Human Rights said at least three people were killed and 18 wounded when security forces and pro-regime militiamen opened fire on protesters as they poured out of mosques.
"One person was killed and three others wounded when security forces opened fire on protesters who emerged from the Mohammadi mosque in Nawa," in the southern Daraa province, the head of the group Rami Abdel Rahman said.
"Two people were killed when pro-regime militiamen opened fire on demonstrators who emerged from the Ali bin Abi Taleb mosque in the eastern oil hub of Deir Ezzor," Abdel Rahman told AFP in Nicosia, Cyprus by telephone.
Rights activists said at least 25 people were shot and wounded nationwide, including five people in Deir Ezzor, six in Al-Qusair near Homs and four in the city itself, among them a father and his four-year-old daughter. People were also injured in Damascus suburbs.
The official SANA news agency said armed masked men attacked security forces in Deir Ezzor wounding three but were later killed in an exchange of fire.
The Local Coordination Committees, a group with people on the ground across Syria involved in organising protests against Assad's regime, also reported massive protests in Qamishli, a Kurdish-populated city in the northeast; Al-Bukamal a town bordering Iraq; and many Damascus suburbs.
Abdel Karim Rihawi, the head of the Syrian League for the Defence of Human Rights who had been jailed earlier this month, said thousands protested in the Sakhur neighbourhood of Aleppo, Syria's second city, in Damascus and in Idlib, in the northwest.
The Syrian Revolution 2011 has urged pro-democracy protesters to rally as well in the evening and through the night Friday in Aleppo to celebrate Laylat al-Qadr - a high point during Ramadan when the Koran was revealed to Prophet Mohammed.
Meanwhile, SANA said police are hunting for the attackers who broke the hand of the country's leading political cartoonist, after Washington condemned the attack.
Cartoonist Ali Ferzat, 60, said four men abducted him while he returned home before dawn Thursday, and broke two fingers of his left hand, his right arm and damaged his left eye.
Opposition activists accused members of the security services and masked pro-regime militias of being behind the attack which the United States described as "disgusting and deplorable."
The UN has been grappling for a response to Assad's bloody crackdowns on protesters, but on Thursday Russia and China boycotted UN Security Council talks on a Western proposal to impose sanctions on Assad, diplomats said.
Russia, which insists that more time should be given to Assad to carry out reforms, agreed earlier this month to back a statement condemning the violence on Syria but has refused along with China and other countries to endorse a formal resolution.
Regionally, the ruler of Qatar, which maintains cordial ties with Damascus, said Syrian use of force to quash dissent is "fruitless" and reforms must be implemented to meet the aspirations of protesters.
Sheikh Hamad was the latest leader from the energy-rich monarchies to pile pressure on Syria and he chose to speak out after talks in Tehran with Iranian President Mahmoud Ahmadinejad, a strong ally of Assad.