In a phase II trial, 36 patients with advanced gastrointestinal cancer were treated with: folinic acid (FA) 500 mg/m2in a 2-hr intravenous (IV) infusion, 5-fluorouracil (5-FU) 600 mg/m2as an IV push injection 1 hr after FA, and hydroxyurea (HU) 35 mg/kg/day given p.o. in three administrations (every 8 hr) 6 hr after 5-FU. Cycles consisted of six weekly treatments for 6 weeks, followed by a 2-week rest period. Thirty-three patients were evaluable for response and 36 for toxicity; 73% had previous chemotherapy. The response rate was 30% (CR + PR), the median duration of response was 21 weeks (range 5–36), and time to failure was 17 weeks (range 3–51). The response in patients previously exposed to chemotherapy was 29% and 44% in chemotherapy-naive patients. The median survival for all entered patients was 28 weeks (range 6–54). The most common toxicity was gastrointestinal: diarrhea 22/36 (61%), mucositis 15/36(42%), and nausea and vomiting 15/36(42%); hematological toxicity was mild. We conclude that HU can potentiate the activity of 5-FU plus FA in advanced gastrointestinal cancer; in particular, HU can restore the activity of 5-FU in patients previously exposed to chemotherapy.