There were 42 patients with advanced gastrointestinal carcinomas (GA) enrolled in the study. In the Phase I part of the study we identified the MTD of 5-fluorouracil (5FU) in combination with levofolinic acid 100 mg/m2 per week intravenously plus hydroxyurea 1 g/m2 per week given by mouth in 3 refracted doses starting 6 hours after 5FU was administered. This treatment was given weekly for 6 consecutive weeks followed by a 15-day rest period. We were not able to increase 5FU weekly dosage above 700 mg/m2 due to the occurrence of grade 3-4 gastrointestinal toxicity. Thus 5FU was employed at 600 mg/m2 per week for the Phase II part of the study. Among 20 evaluable patients with measurable metastatic colorectal cancer, 1 patient had CR of 6.0+ months and 7 patients had PR with a mean duration of 6.2+ months, for an overall response rate of 40%. Four patients (20%) showed stable disease, and 8 patients progressed. The mean survival of the whole group was 5+ months (range: 3.0-12.8). This treatment was very well tolerated by most patients, with grade 3 diarrhea in 10% of cases and grade 3 vomiting in 20% of patients. Hydroxyurea (HU), employed at this dosage, seems not to increase 5FU/FA-related toxicity. This regimen is quite active in the management of advanced colorectal carcinoma, and may be safely given on an out-patient basis. A Phase III randomized trial may be established if HU improves results achievable with the 5FU-FA combination.