One hundred patients with non-small cell lung cancer were entered into a randomized evaluation of two schedules of doxorubicin combined with ftorafur, cyclophosphamide, and cisplatin (FACP). Doxorubicin was given either weekly at 20 mg/m2, or every three weeks (standard) at 60 mg/m2. Fifty-two patients were randomized to the FACP/weekly doxorubicin arm and 48 patients to the FACP/standard doxorubicin arm. The FACP/weekly doxorubicin regimen was associated with higher complete and partial remission rates (31% versus 19%), longer response duration (median, 33 versus 21 weeks), and longer survival duration for responders (median, 58 versus 50 weeks). These differences were not significant. Less neutropenia (p = 0.01) and less infectious morbidity (p = 0.05) were observed in the FACP/weekly doxorubicin arm. Twenty-eight patients underwent 35 endomyocardial biopsies to assess doxorubicin-induced cardiotoxicity. Sixteen biopsies were performed in 12 patients receiving cumulative doxorubicin doses ranging from 250 to 1,190 mg/m2 within the FACP/weekly doxorubicin arm. Nineteen biopsies were performed in 16 patients receiving cumulative doxorubicin doses ranging from 250 to 540 mg/m2 within the FACP/standard doxorubicin regimen. The FACP/weekly doxorubicin regimen was associated with significantly lower cardiotoxicity scores (p = 0.01). This study indicates that weekly administered doxorubicin is as effective and less cardiotoxic than the standard schedule.