We report on two patients with T3N1 rectal cancer treated with a combination of irinotecan, 5-fluorouracil and leucovorin as neoadjuvant chemotherapy. On days 1, 8 and 15 of this 4-week cycle, leucovorin (250 mg/m2) was administered in a 2-hour intravenous infusion, followed by 5-fluorouracil (500 mg/m2) in a 10-min intravenous bolus, and then irinotecan (80 mg/m2) in a 90-min intravenous infusion. During the chemotherapy, no grade 3-4 toxicities were observed. Two weeks after the completion of 2 cycles of this regimen, both patients underwent surgery without postoperative complications. The responses were one pathological and one macroscopic complete response. Both patients with T3 tumors were down-staged to pT0 and pT2, respectively. As for the N stage, both patients were down-staged to pN0. The combination of irinotecan/5-fluorouracil/leucovorin appears to be feasible and effective, and to have a potential as an optimal neoadjuvant therapy in patients with advanced rectal cancer.