The goal of this study was to ascertain the first cycle intolerability rate of the standard Mayo Clinic regimen, 5-fluorouracil (5-FU) 425 mg/m2 with low-dose folinic acid (FA) 20 mg/m2, as a rapid bolus intravenous injection (5-FU/FA) for 5 days every 4-5 weeks for advanced colorectal cancer chemotherapy. The 5-FU/FA arms of 2 large, randomized, controlled trials of 5-FU/FA versus raltitrexed, performed in Europe and North America, were analyzed for intolerability. Two hundred and twelve European patients and 200 North American patients with locally advanced or distant metastatic colorectal cancer were assigned to the Mayo Clinic regimen. During cycle 1, intolerability of the therapy was assessed. Intolerability was recognized as a protocol-driven, toxicity-mandated dose reduction in cycle 2, the inability to complete 5 days of cycle 1 due to toxicity, or failure to receive cycle 2 at all because of toxicity. After the first cycle of chemotherapy, the intolerability rate for the European trial was 41.0% (95% confidence interval [CI], 34.3-47.6) and 49.0% (95% CI, 42.0-56.0) for the North American trial. For the combined 5-FU/FA populations, the intolerability rate was 44.8% (95% CI, 40.0-49.7). The predominant toxicities were stomatitis, diarrhea, and leukopenia. The standard Mayo Clinic regimen was associated with a higher level of dose-limiting toxicities than the accepted maximum of up to 33% for standard chemotherapy.