The authors evaluated the influence of 5-fluorouracil (5-FU) on treatment tolerability in 81 colorectal cancer patients given adjuvant 5-FU intravenously plus folinic acid for 6 cycles. The pharmacokinetics of 5-FU and its inactive metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) were measured on days 1 and 5 of the first chemotherapy cycle, 5 and 45 minutes after bolus administration. 5-FU clearance was significantly lower on day 5 (62.64 ± 20.16 L/h/m2) than on day 1 (74.83 ± 31.61 L/h/m2). The lower 5-FU clearance values also predicted the side effects during the entire course of chemotherapy. In particular, patients with low clearance values on day 1 had a further reduction in this parameter on day 5, associated with severe toxicities. In conclusion, 5-FU alters its clearance, which could be partly due to a reduction in 5-FDHU biotransformation. These findings have safety implications for poor metabolizers whose drug clearance may fall below the threshold during repeated treatment cycles.