Firefighters said it happened around 1:40 a.m. along the 4600 block of Walnut Street, near South 47th Street.
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Officials believe the three victims are related; an uncle and two nephews, but it's unclear which one of them died in the fire. Officials have not confirmed their ages.
Neighbor Kevin Allen said he saw one of the victims hanging from power cables behind the home after the man apparently jumped from a window.
Allen said the cord was cutting into the man's hand.
"I went out in the back driveway and found one of the gentlemen hanging out the back window, kind of wrapped in a power cord or cable cord," said Allen. "His hand was tangled. I got a ladder, pulled him out lifted him up and untangled his hand. Called the fire department."
Allen helped the man to safety.
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Firefighters arrived moments after Allen rescued the first person.
Crews then saw a second person on the roof, so they grabbed ladders and were able to rescue him.
The third person who lived in the home did not make it out alive, officials said.
Assistant Fire Chief Harry Bannan said the home did not have working smoke alarms.
"The fire commissioner and all PFD personnel when we have something like this, we always emphasize the requirement in the city for smoke alarms and the need for your and your family to have working smoke alarms on every level and to practice an escape plan," Bannan said.
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Bannan said every fire they work is sad, especially during holidays.
"You never want to see it any time of year but certainly you don't want to see it on the holidays. For the firefighters and paramedics that respond, it's always difficult," Bannan said.
The two survivors were rushed to the hospital with injuries that include cuts, burns and smoke inhalation.
The fire marshal is investigating the cause of the fire.