After stratification for the extent of disease, previously untreated patients with small cell lung cancer randomized to receive therapy with the four-drug combination of cyclophosphamide, oncovin, nimustine hydrochloride (ACNU), and procarbazine (CONP) every four weeks (continuous regimen) or to receive CONP alternating with the three-drug combination of etoposide (VP-16), adriamycin and cisplatin (VAD) at four-week intervals (alternating regimen). Sixty-nine patients were entered in the study. Of 34 evaluable patients receiving the continuous regimen, six (17.6%) achieved complete response (CR) and 16 (47.1%) achieved partial response (PR). Of 31 evaluable patients receiving the alternating regimen, 10 (32.3%) achieved CR, and 16 (51.6%) achieved PR. There was a tendency in favor of the alternating regimen in CR and over-all response rates (0.05 less than p less than 0.1). There were no significant differences between the regimens in response duration or survival. The projected median survival times were 9.2 months and 9.4 months for the continuous and alternating regimens, respectively. One patient receiving the continuous regimen and three receiving the alternating regimen have been living for more than two years. The major toxicity was myelosuppression in both regimens. One patient died of hemorrhage due to thrombocytopenia during induction with CONP, and one patient died of cisplatin-induced renal failure. We conclude that alternating non-cross resistant chemotherapy leads to improved CR and response rates, but does not improve survival.