Two people were taken to Goulburn Valley Health by ambulance early Thursday after a fire tore through a house on Macisaac Rd in Mooroopna.
A CFA spokesperson said four CFA vehicles, the SES and Ambulance Victoria responded to the call at 1.20am.
The spokesperson said about 80 per cent of the house was involved in the fire, which was brought under control about 1.50am.
CFA District 22 rostered duty officer Peter Bell said he believed four people were home at the time of the fire.
He said the two patients transported to GV Health by ambulance were treated for smoke inhalation.
The house suffered significant structural damage and Mr Bell said it would need to be assessed.
The cause of the fire is undetermined at this point.
Mr Bell said the arson squad and forensic chemists were due to arrive at the scene yesterday afternoon to begin investigating.
Shepparton police confirmed an investigation into the cause of the fire was ongoing and urged anyone who saw or heard anything, or might know something about how the fire started, to phone police on 58205777 or Crime Stoppers on 1800333000.