The rebel-held towns of Madaya and Zabadani in southwest Syria are being evacuated along with the mainly Shia villages of Al-Fu'ah and Kafriya in the northwest.
Madaya and Zabadani are held by anti-government fighters but have been under siege from forces loyal to the regime. The other two villages are government-held but besieged by rebel forces.
More than two thousand rebel fighters, their families and other civilians are in the convoy that left Madaya early Friday in the direction of rebel-controlled Idlib, according to the London-based Syrian Observatory for Human Rights (SOHR).
"The convoy includes at least 60 buses and ambulances carrying the injured and ill people, on board of this convoy there are about 2200 people," SOHR said in a tweeted statement.
The SOHR also said a convoy of 75 buses carrying 5,000 people from Al-Fu'ah and Kafriya had crossed into a part of Aleppo held by the government.
That convoy was earlier seen in Rashidin, an Aleppo suburb that is partly controlled by anti-regime Sunni fighters that had to be crossed in order to reach the parts of Aleppo under government control.
One of the people that left Madaya this morning is Muhammad Darwish, a 26-year-old dentistry student, who was working in a medical facility in the town during the siege.
"It's a long, sad day," he told CNN from the Idlib-bound bus he was traveling on with around 40 other people. "I feel anger, sadness and happiness. Happiness to finish the siege, but now I'm so sad. "
"I don't know what will happen to the people who stayed there and I don't know what will happen to me, or to all my friends who got out with me," he said. "We don't know anything. It's a non-future."
The evacuation of civilians from Zabadani, a southwestern hill station town near the Lebanon border, is expected to begin later on Friday.
The transfers are part of a Shia-Sunni exchange agreement between the government and insurgents who have been fighting a civil war for six years.
The deal was brokered by Iran and Qatar, AFP reported.
The SOHR said parts of Al-Fu'ah and Kafriya came under fire yesterday as people gathered to get on the buses, injuring a woman and a child.
CNN's Eyad Kourdi, Eliza Mackintosh and Deborah Bloom contributed to this report.