Ninety-two patients with advanced non-small cell lung cancer, 51 without prior chemotherapy exposure, were treated with the combination of mitomycin C, lomustine (CCNU), and methotrexate (MCM). Overall, the regression rate was 33%, the median regression duration 4.9 months, and the median survival 4.9 months. Patients with ECOG performance scores (PSs) of 0-1 had a statistically significant higher regression rate than did patients with ECOG PSs of 2-3 (43% versus 15%; p = 0.005) as did patients without prior chemotherapy (41% versus 22%; p = 0.05). Cell type and prior chemotherapy exposure did not affect regression duration, time to progression, nor survival. Subjective toxicity was quite acceptable. Cumulative myelosuppression was the most significant objective toxicity. MCM is a relatively effective combination chemotherapy regimen, even in patients with prior chemotherapy exposure (predominantly doxorubicin and cisplatin-based chemotherapy).