AIM: To evaluate the efficacy and the safety of combined 5-Fluorouracil, irinotecan, bevacizumab and sirolimus in refractory advanced colorectal carcinoma. METHODS: We initiated a regimen with at day 1 an injection (iv) of bevacizumab at 5 mg/kg, followed by 180 mg/m(2) irinotecan, followed by Leucovorin 400 mg/m(2), followed by a 5-Fluorouracil bolus 400 mg/m(2); and a 46-h infusion 2400 mg/m(2). Sirolimus was given orally as continuous administration of 2 mg twice a day every days. This treatment was repeated every 14 d. RESULTS: A total of 12 patients were enrolled. All patients presented with metastatic disease that had failed at least three lines of chemotherapy that contained oxaliplatin, irinotecan and bevacizumab. Cetuximab failure was also observed in all K-Ras wild-type patients. The median number of cycles was 8.5 (range 2-20) and clinical benefit was observed in eight patients. The median time to progression was 5 mo and the median survival was 8 mo. Grade 3 neutropenia developed in four patients, and grade 3 diarrhea and stomatitis in two. CONCLUSION: The combination regimen of 5-Fluorouracil, irinotecan, bevacizumab and sirolimus in advanced colorectal carcinoma after failure of classical treatment is feasible and promising. Further evaluation of this combination is required.