OBJECTIVE This study was undertaken to address the influence of concurrent administration on the pharmacokinetics of UFT (uracil plus tegafur) and leucovorin (LV), and to measure the antitumor activity of a 28-consecutive-day oral regimen of UFT plus LV in patients with relapsed or refractory colorectal cancer. METHODS Patients with advanced measurable colorectal cancer who had failed previous therapy with intravenous bolus 5-fluorouracil (5-FU) were eligible. Patients were treated with UFT 300 mg/m2 per day plus LV 90 mg per day in three divided doses every 8 h for 28 days, repeated at 35-day intervals. In addition, a three-treatment by three-period crossover bioavailability comparison of oral LV 30 mg plus UFT 200 mg versus either LV or UFT alone was scheduled for the 8 days preceding the first cycle of therapy. RESULTS Of 19 patients enrolled, 18 were assessable for pharmacokinetics and response. When LV was coadministered with UFT, there were no statistically significant effects on tegafur, uracil, or 5-FU Cmax, AUC, or Tmax with the exception of a delayed Tmax for tegafur (P=0.03). No statistically significant differences were found in LV and 5-methyltetrahydrofolate plasma levels when LV was administered alone or with UFT. However, wide interpatient variability was observed for all parameters. There were no antitumor responses seen. CONCLUSIONS Although the Tmax for tegafur is delayed with the concurrent administration of LV, there were no differences (P > 0.05) in any pharmacologic parameters that are of likely clinical significance. However, the great interpatient variability observed in UFT and LV pharmacology may have obscured true bioavailability effects in this small patient population. Daily oral UFT plus LV is inactive as second-line therapy in patients who have failed bolus 5-FU.