The fire broke out in the 40-year-old building in Kaohsiung's Yancheng district in the early hours of the morning and was extinguished around dawn.
The Kaohsiung fire department said in a statement that after completing a search of the building they were able to confirm 46 deaths.
Mayor Chen Chi-mai said the building was partly abandoned, having previously been host to restaurants, karaoke lounges and a cinema.
The government is investigating the cause including whether arson was to blame.