Two hundred forty-one patients with unresectable gastric adenocarcinoma were entered, between December 1978 and March 1981, into a prospectively randomized comparison of three chemotherapy regimens to identify therapeutic activity and determine patient tolerability: (1) 5-fluorouracil plus Adriamycin (FA); (2) FA plus methyl-CCNU (FAMe); and (3) FA plus mitomycin C (FAMi). Patients were stratified by stage and performance status prior to randomization. Treatment groups were well balanced with respect to known prognostic discriminants. The primary endpoint to evaluate treatment effect was patient survival. Pair-wise comparisons using a proportional hazards model adjusted for stage and performance status documented a significant survival advantage for FAMe compared with FA (P less than 0.03). Toxicity was primarily hematologic and was seen more frequently in patients receiving FAMe. Further investigations of the FAMe regimen in the surgical adjuvant setting and combined with radiotherapy for patients with locally unresectable gastric cancer are under development.