Biopsy specimens from 19 previously untreated lung cancer patients were prospectively diagnosed as small cell carcinoma with a large cell component. The patients were thoroughly staged and received intensive combination chemotherapy. They represented 12% of all small cell carcinoma cases eligible for aggressive chemotherapy protocols during a 5.5 year period. To determine whether the clinical behavior of this "mixed" histologic variant differed from the other histologic subtypes of small cell lung cancer, we compared these 19 patients to a concurrent group of 103 patients with only small cell cancer in their diagnostic biopsies given equivalent therapy. The "mixed" histology patients were comparable to the "pure" small cell group in age, performance status, extent of disease, and frequency of bone marrow, liver, bone, and central nervous system metastases. Their complete plus partial response rare (58%) was significantly less than the response rate for the "pure" small cell patients (91%), their complete response rate was also lower (16 versus 46%), and their overall survival was significantly shorter (median, 6 versus 10.5 months) Mixed histology small cell/large cell carcinoma represents a distinct pathologic variant of small cell carcinoma of the lung, associated with lower response rates and shorter survival than the "pure" small cell subtypes. Since combination chemotherapy yields some complete responses and long-term disease-free survival in these patients, however, aggressive treatment with potentially curative intent should be considered in their management.