We evaluated the question of whether the chemosensitizers verapamil and quinine given orally to breast cancer patients failing combination chemotherapy alone would result in additional clinical responses. In vitro studies reported here showed verapamil sensitization of Adriamycin resistance in 18.8% of fresh human breast cancer specimens tested. Patients (27) were first treated with cyclophosphamide, vincristine, Adriamycin and dexamethasone (CVAD) alone. Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone. Following treatment with CVAD alone there were no complete remissions and 3 patients (11%) developed partial remissions lasting 5.5, 8, 10.5 months. With the addition of verapamil and quinine to the CVAD regimen, one patient (4%) developed a complete remission of 11.8 months duration and 4 additional patients (15%) developed partial remissions lasting 2.8, 17.3, 19 and > 40 months. Thus, the overall rate of CVAD sensitization by verapamil and quinine was 19%. Treatment with CVAD plus verapamil and quinine was generally well tolerated with observed toxicities including: myelosuppression, neuropathy, Cushingoid symptoms and tinnitus and/or dizziness due to quinine. We conclude that addition of the non-cytotoxic chemosensitizers verapamil and quinine to CVAD in patients failing CVAD alone results in additional clinical responses in a small percentage of patients, some with long term durations. The results of this study lend credence to the notion that non-cytotoxic chemosensitizers can enhance the clinical activity of combination chemotherapy and the search for more effective and less toxic chemosensitizers continues.