In a multicenter phase III trial, 267 patients with nonbulky metastatic colorectal cancer who had failed first-line 5-fluorouracil (5-FU) therapy were randomized to receive second-line treatment with either the new topoisomerase agent, irinotecan (Rhône-Poulenc Rorer, Antony, France), or a high-dose infusional 5-FU regimen. Patients treated with irinotecan survived significantly longer than those treated with infusional 5-FU. The 1-year survival rate was 45% for patients receiving irinotecan compared with 32% for patients receiving 5-FU. There also was a significant difference in median progression-free survival (4.2 months v 2.9 months; P = .03) favoring irinotecan. Irinotecan administered at a dose of 350 mg/m2 every 3 weeks was associated with manageable toxicities (the main toxicities were neutropenia and diarrhea). The incidence of these adverse events and of vomiting was higher with irinotecan than with the comparator regimens of infusional 5-FU. However, the incidence of grade 3-4 asthenia was the same in the two treatment arms and mucositis and cutaneous adverse events were more common with 5-FU. Overall, mean global quality of life scores were similar in the two arms of the study throughout the period of treatment and follow-up, demonstrating that the more effective disease control achieved by irinotecan at least maintains quality of life. Indeed, deterioration in quality of life (defined as >50% decrease from baseline score) occurred significantly later in irinotecan-treated patients. In light of these data, irinotecan should be considered the reference treatment for patients with 5-FU-refractory advanced colorectal cancer.