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 Al-Hayat daily.
The drone programme has come under criticism from human rights activists concerned over civilian casualties.
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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 members of Al-Qaeda, it quoted local security officials as saying at the time.
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 United States 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.
Yemen is the ancestral home of Osama bin Laden and the home base of Al-Qaeda in the Arabian Peninsula (AQAP), which has been linked to a number of failed attacks on the US homeland.
The group has taken advantage of the weakening of the central government since 2011, when a popular uprising erupted that eventually forced president Ali Abdullah Saleh to step down after 33 years in power.