BACKGROUND: We compared the efficacy and toxicity of oral capecitabine and continuous infusion of 5-fluorouracil (5-FU) in the preoperative chemoradiation treatment of patients with rectal cancer. PATIENTS AND METHODS: The files of 89 patients with rectal cancer, 43 treated preoperatively with oral capecitabine and 46 with intravenous 5-FU, were reviewed, and the outcome of the groups was compared. RESULTS: There was no statistically significant difference in the complete pathological response rate between the capecitabine and the 5-FU groups (30% vs. 17%, P = 0.15). The downstaging rate was higher in the capecitabine group (77% vs. 50%, P = 0.009). Toxicity was mild in both groups. The rate of Grade 3 gastrointestinal toxicity was similar in the two groups (diarrhea 2% vs. 4%, proctitis 5% vs. 7%), except for one patient in the 5-FU group (2%) who developed a rectovaginal fistula. In the capecitabine group, one patient (2%) had Grade 3 hand-foot syndrome, and another had an acute myocardial infarction. In the 5-FU group, two patients (4%) had Grade 3 hematological toxicity, and three (6%) had complications from Port-a-Cath insertion. CONCLUSION: Preoperative chemoradiation with oral capecitabine appears to be safe and well tolerated, and at least as good as continuous 5-FU. Copyright 2006 Wiley-Liss, Inc.