The twin-engine plane came apart and caught fire mid-flight, witnesses told local media, before crashing in Yorba Linda, a suburb of Los Angeles.
It is still unclear whether or not the pilot is one of the deceased.
The Federal Aviation Administration said the twin-engine Cessna 414A crashed in Yorba Linda shortly after taking off from the Fullerton Municipal Airport Sunday afternoon.
The aircraft has been identified as a Cessna 414A and had departed the Fullerton Municipal Airport when it went down before 2 p.m. local time.
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The crash occurred in Yorba Linda, the Orange County Fire Authority said on Twitter.
The FAA and National Transportation Safety Board will investigate. However, the OFCA later clarified that only one structure was involved.
Another tweeted: "Pretty sure we just saw a plane crash into a neighborhood".
The number of people in the plane are unknown. Other homes were damaged by debris from the plane, which crashed in the backyard of another home. "It shook our house".
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Two other people were injured in the incident.
Those killed in the home were described as two males and two females, the Orange Country Sheriff's Department said.
Photos and video posted online shows a house in the Southern California neighborhood ablaze with flames, and people running from the area.
Images also showed a propeller and plane debris scattered across a driveway and a man dousing a burning object that was on the street with a garden hose.
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