Officials say it was one of the worst attacks against the U.S. in Pakistan in recent years.
"We pray for the safe recovery of both American and Pakistani victims, and once again we deplore the cowardly act of suicide bombing and terrorism that has affected so many around the world," Secretary of State Hillary Rodham Clinton said during a visit to Indonesia.
The armored SUV from the U.S. Consulate in Peshawar was attacked as it traveled through a heavily guarded area of the city that hosts various international organizations, including the United Nations. The car, driven by the bomber, was packed with 240 pounds of explosives, police said. The blast ripped apart the SUV and started a raging fire.
Two Pakistanis were killed and 19 others were wounded, including police who were protecting the Americans, said senior police officer Javed Khan. The wounds to the Americans were not life-threatening, a U.S. Embassy official said on condition of anonymity because the information had not been officially released.
No group has claimed responsibility for the attack, but suspicion will fall on Taliban and al Qaeda militants, who have long had their sights set on the United States.
The Associated Press contributed to this report.