A man's body was found in the rubble, according to officials.
Due to the incident, W. Roosevelt Blvd. southbound lanes were closed between N . Front and N. Mascher street, but has since been reopened to traffic.
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Neighbors told Action News that squatters have been seen in the vacant home before.
Crews responded to the 100 block of Roosevelt Boulevard around 11:30 p.m. on Sunday. When they arrived, firefighters found heavy fire through the second floor of the home.
The fire struck a second alarm just after midnight.
Neighbors say they saw a man being rescued from a third-floor window of the house next door.
Action News has been told the house was unoccupied at the time of the fire but is attached to another home where the displaced people live.
Chopper 6 was over the scene, where the charred remains of the building could be seen.
Chopper 6 over fatal fire in Philadlephia's Olney section
A man who escaped from the house said the building is broken up into four units and that a number of those residents have been injured.
Officials say four people, including a member of the firefighting team, have been injured and 12 people have been displaced.
Those injured were taken to local hospitals for smoke inhalation. They are all said to be in stable condition.
There has been no word on what caused the fire but the fire marshal is investigating.