The development of drug resistance limits the survival or patients with small cell anaplastic carcinoma of the lung (SCLC). The present study was undertaken to overcome this problem by administering two alternating noncross resistant combination chemotherapy regimens. One-hundred-one patients were entered on study, and 98 were evaluable, with a median onstudy time of 55+ weeks. All patients received the initial combination therapy of cyclophosphamide, methotrexate, and vincristine, alternating every three weeks with Adriamycin and VP16-213 (etoposide). Radiation therapy was not a standard part of protocol. Thirty-two patients had regional disease (LD), and 66 had extensive disease (ED). Overall, 76% of patients responded to this therapy with 30 (31%) complete remission (CR) and 44 (45%) partial remissions (PR); the respective CR and PR rates were 31% and 50% for LD, and 30% and 42% for ED patients. Myelosuppression was the principal toxicity with a leukocyte nadir of 2.0 X 10(9)/1 in 10% of cycles. Septicemia in six neutropenic ED patients with progressive disease contributed to the only treatment-related deaths. Patients entering CR had a median survival greater than 51 weeks (range, 8-150+); 58+ for LD and 49+ for ED patients. Patients in PR had respective median survivals of 33+ (overall), 43+ (LD), and 24+ (ED) weeks. Forty patients have had relapses with initial sites being local sites in 35%, and neurologic in 38%. Although this protocol has not discernibly delayed the onset of drug resistance, the problem should be considered when new protocols are designed in SCLC.