OBJECTIVE To evaluate toxicity and efficacy of addition of weekly irinotecan to a regimen of chemoradiotherapy of 5-fluorouracil with concurrent pelvic radiation in patients with locally advanced rectal cancer. METHODS Between October 2006 and December 2009, 36 patients with non-metastatic rectal adenocarcinoma were treated with chemoradiotherapy of irinotecan (50 mg/m(2) weekly), 5-fluorouracil (250 mg/m(2) for 5 days/week) and pelvic radiation (45 Gy/1.8 Gy/fraction for 5 days/week) by 3D conformal radiotherapy. RESULTS All patients completed the planned treatment. After the chemoradiotherapy, overall clinical response rate was 55.5% and pathological complete was 16.7%. Neutropenia was the most common hematologic toxicity (58.3%) with grade III in 5.5% while among non hematologic toxicity, diarrhea was the most common reported one (63.9%) with grade III in 13.9% followed by nausea and vomiting (47.2%). After a median follow-up of 23 months, progression-free and overall survival estimates at 2 years were 72% and 91.7%, respectively. Distant relapses were recoded in 16.7%, the main distant failure sites were lung and liver, and local relapse was found in 5.6%. CONCLUSIONS Combined chemoradiotherapy of irinotecan, 5-fluorouracil and radiotherapy for locally advanced non metastatic rectal adenocarcinoma is effective and safe. A prospective, randomized trial is needed to confirm these results in larger numbers and to compare this regimen with other non-irinotecan-based chemoradiotherapy regimens.