19 patients with metastatic gastrointestinal malignancy were treated with a regimen of 5-fluorouracil (FU) 500 mg/m2 intravenously and hydroxyurea (HU) 80 mg/kg orally administered on consecutive days weekly. Antitumor responses were not observed and an unusually high incidence of neurotoxicity (21 %) was noted related to dose. It is suggested that the lack of therapeutic effect and the observed toxicity may be related to the biochemical interaction of FU and HU resulting in an inability to convert FU to the active metabolite and an accumulation of catabolic products with neurotoxic effects.