We have carried out a randomized phase III study in 105 patients with advanced non-small cell lung cancer, comparing a four-drug cisplatin-mitomycin-based combination chemotherapy regimen to sequential single-agent therapy. The combination chemotherapy regimen consisted of mitomycin C (10 mg/m2), vinblastine (5 mg/m2), methotrexate (40 mg/m2), and cisplatin (40 mg/m2) given every 28 days. Sequential single-agent chemotherapy consisted of mitomycin C (10 mg/m2) monthly until progression followed by vinblastine (5 mg/m2) every 2 weeks until progression followed by methotrexate (40 mg/m2) weekly until relapse. Patients failing either regimen were followed with supportive care. The objective response rate for the sequential single-agent therapy was 19% versus 25% for the combination chemotherapy group (P greater than .5). The median survival for the single-agent group was 166 days and 191 days for the combination chemotherapy group. Overall survival was not statistically different between the two groups (P greater than .5). Leucopenia, anemia, and prolonged anorexia with nausea and vomiting were more common in the combination chemotherapy group compared to the single-agent group. This study failed to demonstrate a sufficient therapeutic benefit in the face of the added toxicity for the combination chemotherapy regimen compared to sequential single-agent therapy.