The National Cancer Institute of Canada Clinical Trials Group conducted a prospective randomized study comparing standard chemotherapy with alternating chemotherapy in patients with extensive small cell lung cancer. "Standard" treatment consisted of cyclophosphamide (1000 mg/m2 body surface area); doxorubicin (50 mg/m2), and vincristine (2 mg) every 3 weeks for six courses. Alternating chemotherapy was cyclophosphamide, doxorubicin, and vincristine alternating with etoposide (100 mg/m2 on days 1 to 3) and cisplatin (25 mg/m2 on days 1 to 3) every 3 weeks for six treatment cycles. Two hundred eighty-nine patients were eligible and evaluable for response to therapy and survival. Best response was higher in patients on alternating chemotherapy (complete plus partial response, 80% compared with 63.2%; p less than 0.002). Progression-free survival for patients on alternating chemotherapy was superior (p less than 0.0001) as was overall survival (p = 0.03). Major toxicities were equally frequent in both treatment groups. These results show a modest superiority of alternating chemotherapy over standard therapy in extensive small cell lung cancer.