AbstractThirty‐five patients with epithelial carcinomas not considered to be surgically resectable were randomized to receive two different chemotherapy regimens. Regimen 1 was CCNU followed by bleomycin, and Regimen 2 was a combination of CCNU, bleomycin, methotrexate, and vinblastine. Five of 14 patients treated with CCNU‐bleomycin had partial responses. Three of 15 patients treated with the four‐drug combination had a partial response.The toxicity of the four‐drug regimen was significantly greater than that of the two‐drug regimen, while the response rate was greater among those patients treated with two drugs. No significant clinical infections occurred despite the fact that leukopenia and thrombocytopenia were more severe and frequent with the four‐drug regimen.Most importantly, the two‐drug regimen is well tolerated as an outpatient procedure. Two of the two‐drug and one of the four‐drug recipients were converted from an inoperable to an operable state. In view of the fact that there has not heretofore been an effective chemotherapeutic regimen for Stage III and IV squamous carcinoma, this is a significant observation. It is of note that patients with squamous cell carcinoma of the head and neck were those who responded best to this treatment, although the treatment is worthy of consideration for advanced squamous carcino