A Phase I trial of intraperitoneally administered 5-FU and citrovorum factor was performed in eight patients with a variety of malignancies. Both drugs were given according to a single weekly dose schedule in a volume estimated to be 2000 cc, including residual ascites. Citrovorum factor 50 mg was given first, immediately followed by 5-FU 1000-3400 mg, according to a dose-escalating schedule. Myelosuppression proved to be the dose-limiting toxicity, though mucositis, diarrhea, nausea, and abdominal pain were also produced. Six patients failed to respond to therapy. One patient with malignant mesothelioma showed a significant decrease in the production of malignant ascites and a transient conversion of peritoneal fluid cytologies from positive to negative, while a second patient with pancreatic cancer showed conversion of peritoneal fluid cytologies from positive to negative and demonstrated an objective partial response of an hepatic metastasis. Dosage adjustment according to body surface area would seem indicated by the toxicity data, with a 5-FU dose of 1200 mg/m2 body surface area and citrovorum factor 50 mg/m2 being recommended for Phase II trials of this combination of drugs given according to this weekly schedule.