Nineteen patients with adenocarcinoma of unknown primary were treated with the m-FAM regimen, consisting of methotrexate 50 mg/m2 days 0, 28; 5-fluorouracil 600 mg/m2 days 1, 8, 29, 36; Adriamycin 30 mg/m2 days 1, 29; and mitomycin-C 10 mg/m2 day 1. All drugs were recycled every 56 days. No complete responses were seen. Seven patients (37%) achieved partial remission for a median duration of 11 months. An additional nine patients (47%) had stable disease for a median duration of 6 months. Median survival for responders was 16 months and was 10 months for those with stable disease. Toxicity was acceptable. This Phase II study attempted to evaluate the clinical impact of the pharmacological modulation of 5-fluorouracil with methotrexate, the goal being improvement of the results of FAM alone in adenocarcinoma of unknown primary. However, the addition of methotrexate, at least in the schedule employed in this study, did not appear superior to FAM.