It happened shortly after noon Sunday at a two-story home on the 300 block of Main Street in Little Creek, right across the street from the Little Creek Volunteer Fire Company.
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According to Fire Chief Michael Scott Bundek, firefighters responded within one minute of getting the call.
They received reports of people trapped inside the home.
Crews located the 9-year-old and two other victims.
Chief Bundek said one person jumped out a second-floor window before firefighters arrived to escape the flames.
The Delaware Office of the State Fire Marshal said five victims were taken to Bayhealth Hospital - Kent Campus in Dover for smoke inhalation and burns.
The 9-year-old girl and a 42-year-old woman died at the hospital, the Fire Marshal said.
Three other victims remain in critical condition.
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The Fire Marshal said two of those victims were expected to be transferred to the Crozer-Chester Medical Center in Upland, Pennsylvania.
Authorities have not identified the victims.
The cause of the fire remains under investigation.
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