A Phase I study was conducted of 5-fluorouracil administered i.p. in a 2-liter volume of 1.5% Inpersol. The drug was administered via Tenckhoff peritoneal dialysis catheters to ten patients with tumors confined to the i.p. space. Dialysis concentrations ranged from 5 micro M to mM. Complications of the dialysis procedure alone included mild abdominal discomfort and 2 cases of gram-negative bacterial peritonitis, both easily controlled with antibiotics. 5-Fluorouracil caused the same pattern of toxicity as when administered by other routes. There was no local or central nervous system toxicity. Dose-limiting toxicity included pancytopenia and mucositis at a dialysis concentration of 4.5 to 5 mM administered for eight consecutive 4-hr exchanges. There were two documented responses in eight evaluable patients. 5-Fluorouracil concentrations were measured by high-pressure liquid chromatography. Peritoneal fluid concentrations decline in a first-order fashion with a half-life of 1.6 hr. The mean permeability area product was 14 ml/min. A mean of 82% of drug was absorbed in 4 hr. Plasma levels rise over the first 30 to 45 min and decline in a nonlinear fashion. Plasma levels are substantially lower than are peritoneal fluid levels. Mean 4-hr peritoneal fluid concentration was 298 times the simultaneously measured plasma levels. Total body clearance ranged from 0.9 to 15 liters/min and declined with increasing dialysate concentration. We conclude the i.p. route is a relatively safe way to deliver high concentrations and large amounts of drug to the i.p. cavity with a significant pharmacological advantage over conventional routes of administration.