The unidentified victims, sisters ages 3 years and 6 months, were found on the third floor of the large, five-family house, State Police Lt. J. Paul Vance said.
Four people were injured in the fire, which began early Tuesday and took 5 hours to extinguish, the Hartford Courant reported.
The mother of the girls, who is pregnant with twins, was initially taken to a local hospital but was transferred to the UMass Memorial Medical Center in Worcester, Mass., Assistant Fire Chief Norm Perron said, adding that three residents suffering smoke inhalation were taken to a Putnam hospital.
Witnesses said the fire started on the top floor of the house, which Putnam Mayor Peter Place said was built in 1887.
Damage to the house was severe, a fire department spokesman said.
Perron added it was too soon to identify the cause of the fire.