There were no immediate reports of casualties among U.S. or North Atlantic Treaty Organization forces.
Afghan officials said the attack happened shortly after 7 a.m. near the entrance to Forward Operating Base Chapman in Khowst, a province near the border with Pakistan that is a hotbed of insurgent activity.
The bomber detonated a minivan packed with explosives when stopped by Afghan security guards at a checkpoint on a road leading to the base, said Provincial Police Chief Abdul Qayoum Baqizoy. One of the guards and two civilian drivers were killed in the blast, which also injured six other people, he said.
"It is important to note that there was not any breach of the [base] perimeter," said Charlie Stadtlander, a spokesman for the International Security Assistance Force in Afghanistan.
In December 2009, a double-agent-turned-bomber slipped into the base and detonated a suicide vest, killing seven CIA employees in the largest single-day loss for the spy agency in three decades.
The Taliban took responsibility for Wednesday's attack in a statement posted on its website, claiming that more than 100 "enemies" were killed. The insurgents routinely exaggerate the effects of their attacks.
The statement, attributed to spokesman Zabiullah Mujahid, identified the attacker as a resident of Khowst province named Omar.
"According to our information, every day more than 250 Afghan enemies are waiting to be searched and go into the base to serve the Americans in exchange for dollar salaries," the statement said. "They are playing with their country, religion and honor."
Hashmat Baktash is a Times special correspondent