Militants linked to al Qaeda, angered by her support for the US war on terrorism, had threatened to assassinate her.
Earlier, she pledged to fight for democracy as she ended her exile amid chaotic scenes at Karachi airport.
With tears in her eyes as she walked off the plane that had brought her from Dubai, Ms Bhutto waved at supporters and said: “I feel good.”
She then stood atop a vehicle specially made for her journey from a shipping container as crowds cheered her.
She said: “I counted the hours, the minutes and the seconds just to see this land, sky and grass.”
More from the scene via AP:
An Associated Press photographer at the scene said he saw between 50 and 60 dead or badly wounded people. He said some of the bodies were ripped apart.
An initial small explosion was followed by a huge blast just feet from the front of the truck carrying Bhutto during a procession through Karachi. The blast shattered windows in her vehicle.
Footage from the scene showed bodies on the ground, lying motionless, plus a dozen or more injured who were moving.
Several motorcycles also lay on their sides. Flames burned in the center of the street after the explosions.
Scores of people, mostly men wearing white robes, fled down the street after the blast.
Neither Bhutto nor any of the others riding on the truck was hurt, police officer Hasib Beg said.