The Mayo Clinic regimen of leucovorin 20 mg/m followed immediately by 5-fluorouracil 425 mg/m administered for 5 consecutive days every 4 weeks is commonly used in the treatment of colorectal cancer. This study was aimed at prospectively determining the incidence and pattern of severe toxicity associated with this regimen. We evaluated prospectively 243 patients with colorectal cancer treated in our department with the Mayo Clinic regimen for the incidence of severe toxicity (defined as toxicity requiring hospitalization). Of the 243 patients, 32 (13%) were hospitalized for chemotherapy-related toxicity. Major toxicities included neutropenic fever in 21 (9%), grade III/IV mucositis in 25 (10%) and grade III/IV diarrhea in 20 (8%). There were five (2%) treatment-related deaths. Female patients exhibited a higher incidence of severe toxicity (18%) and toxic death (4/105) than did male patients (9% and 1/138, respectively). Elderly patients (> or =70 years) had a higher incidence of severe toxicity than younger patients did (24% versus 7%, < 0.001). Toxic death occurred in 4 of 89 patients aged 70 years or more compared to 1 of 154 in younger patients. Most episodes of severe toxicity (56%) and toxic deaths (4/5) were observed after the first cycle. We conclude that the Mayo Clinic regimen can be associated with severe toxicity, usually occurring after the first cycle. Female gender and advanced age predict severe toxicity; therefore, dose reduction in high-risk patients should be considered, especially during the first cycle.