There were conflicting casualty reports, The New York Times reported.
"No U.S. Consulate personnel were killed," a statement issued by the U.S. Embassy in Islamabad said. "Two U.S. personnel and two Pakistani staff were injured."
A senior Pakistani government official said two Pakistanis were killed but denied a statement issued earlier by local officials in Peshawar that Americans had also died.
"The Americans were traveling in an armored SUV and survived the attack," the official told The New York Times.
The official said another consulate vehicle retrieved the injured Americans and returned to the diplomatic compound.
No one immediately claimed responsibility for the attack.
The consulate vehicle left the heavily guarded building and was passing a U.N. United Nations High Commissioner for Refugees guesthouse when it was crashed into by a vehicle carrying at least 200 pounds of explosives, police said.
Smoke from the explosion could be seen a mile away, witnesses said. The blast left a 5-foot crater in the road.
Officials said the explosion damaged several other vehicles and five to six nearby buildings.
Sources told Dawn there had been recent threats of an attack on the U.S. Consulate and since then security had been put on high alert.