A drone strike Saturday killed 15 Al-Qaeda suspects and three civilians in Yemen's central Baida province, a stronghold of the extremist group, a security official said.
The jihadists were travelling in a vehicle towards the southern Shabwa province, witnesses said. The three civilians were passing by in another car.
The United States is the only country that operates drones in Yemen, but officials rarely discuss the covert programme.
Last month, Yemen's President Abdrabuh Mansur Hadi defended the use of drones against Al-Qaeda in his country, which has killed dozens of militants in a sharply intensified campaign over the past year.
Drone strikes "have greatly helped in limiting Al-Qaeda activities, despite some mistakes, which we are sorry about," Hadi told the pan-Arab daily Al-Hayat.
The drone programme has come under criticism from human rights activists concerned over civilian casualties.
The United Nations said 16 civilians were killed and at least 10 wounded when two separate wedding processions were targeted in December.
The victims had been mistakenly identified as Al-Qaeda members, it quoted local security officials as saying at the time.
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Following the deaths, Yemen's parliament voted for a ban on drone strikes, but analysts say lawmakers are unlikely to be able to halt the US campaign.
The US has defended the drone campaign, which allows it to target Al-Qaeda without the use of ground forces in lawless areas where authorities cannot or will not act against the group.
Militants regularly attack security forces from hideouts in the mountainous terrain of Baida.
On Tuesday, Qaeda suspects shot dead the province's vice governor and an intelligence officer.
Tribal ources in the region claim a recent video of Al-Qaeda in the Arabian Peninsula chief Nasser al-Wuhayshi welcoming 19 militants who escaped a Sanaa prison was filmed between Shabwa and Baida.
Addressing scores of jihadists in the rare video appearance, Wuhayshi pledged to pursue the war against Western "crusaders" everywhere possible.
In the February jailbreak, AQAP militants slammed a car bomb into the eastern gate of a Sanaa prison as others attacked the guards at its main entrance. The attack allowed 29 inmates to escape, including the 19 jihadists.
Yemen is the ancestral home of Osama bin Laden and the home base of AQAP, which has been linked to a number of failed attacks on the US homeland.
The group has taken advantage of the weakening of Yemen's central government since 2011, when a popular uprising erupted that eventually forced president Ali Abdullah Saleh to step down after 33 years in power.