The U.S. said it would review its security procedures following Monday's attack, which was condemned by Secretary of State Hillary Rodham Clinton.
"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," 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. It was unclear how the bomber penetrated the area and knew which vehicle to attack.
The car driven by the bomber was packed with 110 kilograms (240 pounds) of explosives, police said. The blast ripped apart the SUV tossing its engine at least 6 meters (20 feet) away and started a raging fire. Rescue workers and residents rushed to put out the fire and pull away the dead and wounded. All that was left of the SUV was a charred mass of twisted metal with a red diplomatic license plate.
The SUV's driver, Atif Nawaz, said the blast knocked him out.
"When I came to my senses, I jumped out of my car and screamed, 'What happened?'" said Nawaz, whose face and hands were badly burned.
The attack killed two Pakistanis and wounded 19 other people, including police who were protecting the Americans, said senior police officer Javed Khan.
Two Americans and two Pakistanis working at the U.S. Consulate in Peshawar were among the wounded, said State Department spokeswoman Victoria Nuland, who called the attack a "heinous act."
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.
The charge d'affaires at the U.S. Embassy, Richard Hoagland, praised Pakistani security forces for saving the lives of the four consulate employees.
"In this dangerous world where terrorists can strike at any moment, we must all work together Pakistanis and Americans alike because we have a strong mutual interest in defeating terrorism," he said.
No group has claimed responsibility for the attack, but suspicion will fall on Taliban and al-Qaida militants who have long had their sights set on the United States. American drones have fired scores of missiles at the militants' hideouts in Pakistan in recent years, and Washington has given the Pakistani military billions of dollars to fight the extremists.
The worst recent attack on U.S. personnel in Pakistan was in 2010 when a suicide car bombing in the northwest area of Lower Dir killed three American soldiers who were training local forces.
A car bomb and grenade attack against the U.S. Consulate in Peshawar in April 2010 killed four Pakistanis, including three security personnel and a civilian. In August 2008, the top U.S. diplomat at the consulate survived a gun attack on her armored vehicle. Three months later, gunmen shot and killed an American in Peshawar as he was traveling to work for a U.S.-funded aid program.
Peshawar, located some 135 kilometers (85 miles) from Islamabad, has long been a vital hub for U.S. interests in the region. It is the capital of Khyber Pakhtunkhwa province and is located on the border of Pakistan's semiautonomous tribal region, the main sanctuary for Taliban and al-Qaida militants in the country.
Much of the funding that was handed to Afghans fighting Soviet troops in neighboring Afghanistan in the 1980s was channeled through Peshawar. The city's proximity to the tribal region made it an important place for American officials to be based following the Sept. 11, 2001, attacks that led to the invasion of Afghanistan. Many militants have used the tribal region as a base to attack U.S.-led forces in Afghanistan.