The combination of mitomycin C, methotrexate, cisplatin, and vinblastine was administered to 45 patients with unresectable non-small cell lung cancer. Thirty-nine patients satisfied criteria for assessment of response to chemotherapy. All patients had a performance status of greater than 50%, had evaluable disease, and had not received previous chemotherapy. The overall response rate was 54% with responses seen in 12 of 19 squamous cell, 8 of 16 adenocarcinoma, and 1 of 4 undifferentiated large cell lung cancer patients. Median survival was increased by 3 months in those patients with an objective response to chemotherapy. Drug-associated toxicity was rare, but apparent mitomycin C-related pulmonary fibrosis was observed in two patients. This four-drug combination was shown to be an active regimen in the treatment of non-small cell bronchogenic carcinoma.