The explosion occurred at the Hajan Shah Mauri Dargah near Shikarpur when a large number of people were visiting the shrine.
The blast came just five days after an Islamic scholar was targeted in a bomb attack at Jacobabad in Sindh.
Witnesses told the media they had seen a man going out of the shrine after leaving a bag.
The explosion occurred shortly after the man left the shrine, one witness said.
The custodian of the shrine was among the injured, who were taken to the Civil Hospital in Shikarpur city.
Angry devotees and local residents took to streets and shut down Shikarpur city after the bombing.
Additional police forces were deployed around the shrine.
On February 20, Sain Hussain Shah, the Pir of Qambar Sharif, was targeted in a bomb attack near Jacobabad.
Shah's grandson was killed and 10 others were injured in the attack.
Islamabad: A bomb blast ripped through a gathering at a Sufi shrine in Pakistan's southern Sindh province on Monday, killing four persons and injuring 12 others, police said.
First Published: Monday, February 25, 2013, 22:43