A controlled clinical trial comparing two-drug and three-drug combination chemotherapy was performed in 206 patients with advanced bronchogenic carcinoma, comprised of 26.2% with epidermoid carcinoma, 30.1% with small cell anaplastic carcinoma, 27.2% with adenocarcinoma, and 15.6% with large cell carcinoma. Each drug combination consisted of agents with different modes of action and included a cell-cycle-stage nonsensitive and a cell-cycle-state-sensitive agent. The overall response rate was highest for small cell carcinoma (48.2%) and adenocarcinoma (23.6%); it was less than 10% in epidermoid and large cell carcinoma. Similarly, the overall median survival was twice as long for the first two cell types (7 months) as compared with that recorded for the other two cell types (3 1/2 months). The combination of 1 (2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cyclophosphamide, and methotrexate was shown to be statistically superior to cyclophosphamide and methotrexate with regard to objective respones rate, duration of response, and median survival for adenocarcinoma. Responders lived significantly longer than nonresponders (254 versus 90 days for small cell anaplastic carcinoma patients and 244 versus 184 days for adenocarcinoma patients). No difference in survival or objective response rate was observed between the different treatments for the other two cell types of lung cancer.