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Firefighters faced heavy smoke and flames when they arrived to the burning home on Modena Place, Fire Commissioner Adam Thiel said.
Inside firefighters found a married couple dead, Philadelphia police said.
Investigators are searching for a cause for the fire.
A bedridden husband and wife died in a house fire that injured their adult daughter and son-in-law.
Authorities on Tuesday tried to determine what sparked the blaze that broke out around midnight in the two-story dwelling on Modena Place in Northeast Philly.
Firefighters faced heavy smoke and flames when they arrived on the scene, Fire Commissioner Adam Thiel said.
Firefighters discovered the a 78-year-old man and his 68-year-old wife dead on the first floor, Philadelphia police said.
Their 46-year-old daughter and 46-year-old son-in-law were taken to a hospital and are in stable condition with burns and smoke inhalation, police said.
"A very tragic night for us," Thiel said.
No names have been released.
Neighbors said the couple had health problems that required oxygen tanks. The daughter and her husband cared for them.
The fire marshal was on the scene early Tuesday to help determine a cause for the blaze.