Oxipurinol, the major metabolite of allopurinol, decreased the toxicity of 5-fluorouracil (5-FU) to human granulocyte colony-forming units in vitro by a factor of four. The ability of allopurinol to reduce 5-FU toxicity in vivo was studied in 23 advanced cancer patients during 42 courses of treatment. 5-FU was administered by continuous intravenous infusion for five days; allopurinol, 300 mg, po, every 8 hours was started 2 hours before and continued during and for 24 hours after 5-FU infusion. 5-FU was escalated from 1.5 to 2.25 g/m2/day on separate courses; the dose-limiting toxicity was mucositis which occurred at a level of 2.0 g/m2/day. At a 5-FU dose rate of greater than 2.0 g/m2/day 5-FU pharmacokinetics were nonlinear, reflecting saturation of catabolic pathways, and the steady-state 5-FU serum concentration was approximately 4 times that which was tolerable without allopurinol. At these concentrations of 5-FU oxipurinol significantly influenced the clearance of 5-FU. Thus concurrent allopurinol therapy permitted a doubling of the maximum tolerated dose of 5-FU and a four-fold increase in the tolerated concentration x time exposure to 5-FU.