In this study, we evaluated the role of alternating chemotherapy with or without etoposide (VP-16) in patients with extensive-stage small-cell carcinoma (SCC) of the lung. All patients received initial treatment with CMC [cyclophosphamide, methotrexate, and chloroethyl-cyclohexyl-nitrosourea (CCNU)]. Four weeks after initial treatment, patients were stratified by performance score, central nervous system (CNS) metastasis, age, and response to initial CMC therapy and randomized to receive AO (doxorubicin and vincristine) or AVO (doxorubicin, VP-16, and vincristine) alternating with CMC. One hundred eighty-two eligible patients were treated with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to either AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly different on the two treatment regimens. Toxicity was significantly greater for patients receiving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression, or survival of patients with extensive small-cell lung cancer.