Twenty-three patients with small cell carcinoma of the lung (15 with limited disease and eight with extensive disease) were randomized into one of two induction schedules of high-dose cyclophosphamide (CY), 60 mg/kg iv, given either on Days 1 and 2 or on Days 1 and 8. Following the high-dose CY, patients were treated with a sequence of three monthly courses of COMB (CY, 800 mg/m2; vincristine [Oncovin], 1.4 mg/m2; methotrexate, 20 mg/m2; and BCNU, 60 mg/m2) alternating with high-dose CY. The overall response rate to the high-dose CY was 70% with 17% being complete responses (CRs). COMB produced no additional responses. There was no significant difference in response rate with either high-dose CY schedule. There was no unexpected morbidity associated with the intensive regiment despite marked myelosuppression. The high-dose CY administered on Days 1 and 8 appeared less toxic than that given on Days 1 and 2. Laboratory studies demonstrated that small cell carcinoma cells respond to drug-induced humoral stimulation in vitro; and that tumor proliferation in vivo temporally coincides with increased serum stimulatory activity. This study demonstrates that high-dose CY is a safe and effective induction therapy for small cell carcinoma of the lung although the low CR rate obtained is disappointing.