Firefighters were called to the blaze in Withington, Manchester, at about 2.20am this morning.
A Greater Manchester Police spokesman said a man and a woman died at the scene.
Three girls and a boy, aged between 10 and 17, were taken to hospital, where they are being treated for their injuries.
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Two people have died in hospital after firefighters were called in Manchester early this morning
Another man was also taken to hospital and he remains in a serious condition.
My thoughts are with the family of the man and woman after such a tragic incident
Detective Inspector Tony Lea
Police have launched a joint investigation with Greater Manchester Fire and Rescue Service (GMFRS) to establish the cause of the blaze.
Detective Inspector Tony Lea said: "My thoughts are with the family of the man and woman after such a tragic incident and we have specially-trained officers supporting the family at this time.
"We are continuing to work closely with GMFRS to establish exactly how this fire started and I urge anyone who may have witnessed the fire, or anyone in the area in the hours before the fire.
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Police have launched an investigation into the cause and are appealing to the public for information
"If you have any information at all contact police as soon as possible so we can piece together what happened."
The force spokesman said next of kin had been informed but the bodies had yet to be formally identified and post-mortems had not yet taken place.
Anyone with information should contact police on 101 quoting incident number 140 10/02/17 or the independent charity Crimestoppers, anonymously, on 0800 555 111.
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