Irinotecan (CPT-11, Camptosar) is one of the new generation of chemotherapeutic agents that has activity in advanced colorectal cancer. It has antitumor efficacy as a single agent, and also has been combined with fluorouracil (5-FU) and leucovorin (IFL) to treat these patients. Randomized studies have confirmed the superiority of IFL to 5-FU and leucovorin alone with regard to patient survival, time to progression, and tumor response rate. The optimal schedule for combining these agents remains uncertain, but in the United States, the schedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks, according to the schedule reported by Saltz et al, has been widely used, although with some toxicity (especially myelosuppression and diarrhea). In an attempt to improve the tolerability of IFL, some have advocated modifying the schedule of IFL to weekly for 2 weeks, with repeated cycles every 21 days. Twenty-three patients with advanced colorectal cancer have been treated on this schedule at a single institution. Therapy was well tolerated, with 35% of patients experiencing grade 3/4 neutropenia, two of whom had episodes of febrile neutropenia, and 9% with grade 3/4 diarrhea. The median relative dose intensity of irinotecan administered in the first 18 patients treated with this regimen was 94%. These data support the hypothesis that modifying the schedule of administration of IFL improves the tolerability and ability to deliver the regimen, but must be confirmed by randomized prospective studies, which may also attempt to evaluate the role of bolus 5-FU in the treatment of advanced colorectal cancer.