It was not immediately clear who planted the device at the small mosque belonging to a Shia community in the town of Dera Ismail Khan.
"Four people were killed and two others were injured when a timed explosive device went off at a mosque," Abdul Ghaffar Qaiserani, a district police chief, said.
He also said that people were coming out of the mosque after prayers when the blast went off.
The blast shattered the mosque's front wall and damaged its dome.
Twisted fans hung from the ceiling inside the mosque and prayer mats were scattered across the bloodstained floor.
Police cordoned off the area as people sifted debris looking for survivors.
Shias account for about 20 per cent of Pakistan's 160 million, predominantly Sunni population.
The groups usually co-exist peacefully but outbreaks of sectarian violence involving fighters from both sides have claimed more than 4000 lives across Pakistan since the late 1980s.