UFT (with leucovorin) and irinotecan both have single-agent activity in colorectal cancer, with non-cross-resistant mechanisms of action. Combining these drugs would be anticipated to increase response rates while maintaining the advantages of a regimen based on an orally administered fluoropyrimidine. This trial aims to determine the maximum tolerated dose, side-effect profile, dose-limiting toxicity, and response rate for the combination of UFT plus leucovorin, and irinotecan. The design is for an initial phase I study investigating escalating doses of UFT (250 to 350 mg/m2/d) and irinotecan (200 to 300 mg/m2) with fixed doses of leucovorin at 90 mg/d, in up to five cohorts of six patients each. UFT and leucovorin are given orally on days 1 to 14 of a 21-day cycle and irinotecan is given intravenously on day 1. The maximum tolerated dose is defined as the dose at which three of six patients in a cohort have a dose-limiting toxicity in the first cycle of treatment. In the second part of the study, the cohort below that experiencing maximum tolerated dose will be expanded up to a total of 20 patients in order to assess further the toxicity and response rate (phase II). To date, 17 assessable patients have been recruited, with a median age of 64 years (range: 35-80 years). At the first dose level (UFT 250 mg/m2/d and irinotecan 200 mg/m2), no dose-limiting toxicities were seen, and in cohort 2 (UFT 250 mg/m2/d and irinotecan 250 mg/m2), there was one grade 3 diarrhea. In cohort 3 (UFT 250 mg/m2/d and irinotecan 300 mg/m2), currently there have been two grade 3/4 toxicities (both neutropenic fever). Thus, the maximum tolerated dose has not yet been reached. Response has been assessed in the first six patients, with three having partial response, two having stable disease, and one having progressive disease (response rate 50%). We conclude that this regimen appears feasible with acceptable toxicity at these dose levels. There is also evidence of significant antitumor activity similar to that seen with other fluoropyrimidine-based combination regimens but without the requirement for indwelling catheters or inpatient admission.