"Five American troops were killed at about noon when their armoured vehicle hit a powerful roadside mine in Maiwand district," Kandahar police chief General Abdul Razeq said.
The troops died in an improvised explosive device (IED) attack, NATO's International Security Assistance Force confirmed in a statement without specifying the nationalities of the victims, in line with coalition policy.
The attack came four days after three British forces were killed in a similar attack in the neighbouring province of Helmand.
There was no immediate claim of responsibility but Taliban militants frequently use roadside bombs against US-led foreign troops.