In a prospective randomized Eastern Cooperative Oncology Group (ECOG) study, 53 eligible and evaluable patients with advanced gallbladder carcinoma and 34 with advanced bile duct carcinoma were treated with oral 5-fluorouracil (5-FU) or with oral 5-FU plus streptozotocin (Stz) or oral 5-FU + Methyl-CCNU (MeCCNU). Severe toxicity occurred in 2 of 30 patients receiving 5-FU (7%), in 14 of 26 receiving 5-FU + Stz (54%), and in 12 of 31 receiving 5-FU + MeCCNU (39%). Five of 53 patients with gallbladder carcinoma (2/18 [11%] on 5-FU, 2/16 [12%] on 5-FU + Stz, and 1/19 [5%] on 5-FU + MeCCNU) had objective response to treatment. There was no significant difference between treatments with respect to response or survival. Three of 34 patients with bile duct cancer (1/12 [8%] on 5-FU, 0/10 on 5-FU + Stz, and 2/12 on 5-FU + MeCCNU) had objective response to treatment. There was no significant difference between treatments with respect to response or survival. Patients with prior chemotherapy were randomized between MeCCNU alone and Stz alone. Among such patients, only 1 of 17 patients who had prior chemotherapy with other agents responded to MeCCNU alone, and none of 14 patients responded to Stz alone.