BACKGROUND: Recent pharmacoepidemiology data show an increase in the proportion of patients receiving second-generation antipsychotic (SGA) monotherapy, but no studies have analyzed the same patients over a long period of time. Therefore, in this study, we decided to evaluate retrospectively schizophrenia patients with available data for 20 years to see whether the drug treatments in the same patients have changed in the past 20 years. METHODS: The study began in April 2021 and was conducted in 15 psychiatric hospitals in Japan. Schizophrenia patients treated in the same hospital for 20 years were retrospectively examined for all prescriptions in 2016, 2011, 2006, and 2001 (i.e., every 5 years). RESULTS: The mean age of the 716 patients surveyed in 2021 was 61.7 years, with 49.0% being female. The rate of antipsychotic monotherapy use showed a slight increasing trend over the past 20 years; the rate of SGA use showed a marked increasing trend from 28.9% to 70.3% over the past 20 years, while the rate of SGA monotherapy use showed a gradual increasing trend over the past 20 years. The rates of concomitant use of anticholinergics, antidepressants, anxiolytics/sleep medications, and mood stabilizers showed decreasing, flat, decreasing, and flat trends over the past 20 years, respectively. CONCLUSION: The results of this study showed a slow but steady substitution of SGAs for first-generation antipsychotics (FGAs) over time, even in the same patients.