OBJECTIVE: The chemotherapy regimen suitable for advanced colorectal cancer patients previously treated with 5 fluorouracil (5FU); oxaliplatin and irinotecan remains an unresolved issue. The poor response rates and progression-free survival achieved with FOLFIRI in the second-line of therapy and the schedule-dependent activity of irinotecan, prompted us to assess the efficacy and tolerability of FOLFIRI3 regimen in patients with metastatic colorectal cancer (CRC) previously exposed to irinotecan and oxaliplatin. METHODS: Twenty-seven metastatic CRC patients previously exposed to irinotecan and/or oxaliplatin were treated with the FOLFIRI3 regimen. They received an irinotecan injection at 100 mg/m(2) before and at the end of a 2400 mg/m(2) 5FU continuous infusion. Two hundred and six cycles of chemotherapy were delivered in an outpatient basis. RESULTS: FOLFIRI3 regimen was well tolerated. Grade 3 of 4 adverse events included nausea and vomiting (18%), diarrhea (11%), anemia (7%), and neutropenia (7%). Partial responses were observed in 2 patients and 10 patients achieved stable diseases. From the start of FOLFIRI3, time to progression was 4.47 months (0-11 months) and median overall survival was 8.9 months (0.72-21.4 months). Interestingly, FOLFIRI3 treatment was associated to a clinical benefit in 7 out of 17 patients who previously progressed "on-therapy" or less than 3 months after the completion of a previous FOLFIRI chemotherapy. CONCLUSION: These results suggest that fractionated irinotecan administration might restore the clinical benefit of this molecule in patients resistant to FOLFIRI.