Men, women and children packed onto buses leaving government-controlled Fuaa and Kafraya and rebel-held Madaya and Zabadani, with many expressing despair at not knowing when they might return.
"When I first went onto the bus, I broke down from sadness, I fell on the ground and they had to help me," said Fuaa resident Abu Hussein.
"I just couldn't bear it."
The deal to evacuate the towns is the latest in a string of such agreements through Syria's six-year civil war.
Critics say deals are permanently changing the ethnic and religious map, but in an exclusive interview with AFP this week President Bashar al-Assad insisted the evacuations were only temporary and people would return once the "terrorists" had been defeated.
At least 80 buses left Fuaa and Kafraya in Idlib province
In the northwest, an AFP correspondent in rebel-held territory said.
They arrived at a marshalling point in Rashidin, west of second city Aleppo, followed by 20 ambulances.
The Observatory said 2,200 people from Zabadani and Madaya had left, among them 400 rebels.
Madaya resident Amjad al-Maleh, speaking from a departing bus, told AFP that rebels among the evacuees had been allowed to keep light weapons.
"It is a very bad feeling when you see those who besieged you and killed you with hunger and bombardment right in front of you," Maleh said.
"Madaya cried today -- the ones who stayed and the ones who left."
Late Friday, the buses from Madaya arrived in Rashidin, where the evacuees from Fuaa and Kefraya were waiting, according to a resident aboard one of the buses.
More than 30,000 people are expected to be evacuated under the deal, which began on Wednesday with an exchange of prisoners.
All 16,000 residents of Fuaa and Kafraya are expected to leave, heading to Aleppo, the coastal province of Latakia, or Damascus.
Civilians from Madaya and Zabadani will reportedly be allowed to remain if they choose. Those who opt to leave will head to rebel-held territory in Idlib.
The four towns are party to a longstanding agreement reached in 2015 that requires aid deliveries and evacuations to be carried out simultaneously.
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