One hundred ninety-six patients with advanced pancreatic cancer were randomized to receive one of two combination chemotherapy programs: FAM (5-fluorouracil, Adriamycin [doxorubicin], mitomycin) or FSM (5-fluorouracil, streptozotocin, mitomycin). Patient characteristics were comparable in both groups. Overall response rates for those with measurable disease (14% on FAM, 4% on FSM) were not significantly different (P = 0.07). There was no significant difference in overall survival between patients treated with FAM and FSM (median survivals of 26 and 18 weeks, respectively). Survival benefits of FAM were significant only for patients with measurable disease. Toxicity of both regimens was acceptable and comparable, aside from greater renal toxicity and more nausea and vomiting with FSM. The results failed to confirm the 35% to 40% response rates previously reported for FAM and FSM in advanced pancreatic cancer.