Introduction: The aim of this retrospective, observational study was to assess the efficacy of the reintroduction of irinotecan and oxaliplatin as a combination (IROX regimen) in heavily pretreated colorectal cancer patients. Patients & Methods: Patients were eligible for the study if they had already been treated with oxaliplatin, irinotecan, bevacizumab and cetuximab or panitumumab (if K-RAS wild type or unknown status). Starting doses of irinotecan and oxaliplatin were 180 mg/m2 and 85 mg/m2 respectively, every 2 weeks but in case of poor performance status or a history of side-effects from previous chemotherapy regimens, lower doses were given and at longer intervals. Assessment was done every 5 to 6 cycles. Control disease rate (CDR), progression free survival (PFS) and median overall survival (OS) were calculated. Results: Twenty five patients with a median number of 3 previous chemotherapy regimens were included in the study. The median number of metastatic sites per patient was 2. Seventy six percent of the patients received treatment at reduced doses. Neutropenia (16%), diarrhea (12%) and fatigue (8%) were the more common severe (grade 3 and 4) side-effects. One patient had partial response of his disease (4%) and 7 patients showed stabilization of their disease (28%) (CDR: 32%). Control of the disease was noticed in 27% of patients with refractory disease to both irinotecan and oxaliplatin. Median PFS and median OS were 3 (95% confidence interval 2.3-3.7) and 7 (95% confidence interval 6.2-7.8) months respectively. Conclusions: Reintroduction of IROX chemotherapy every two weeks produces a 32% CDR and a 7-month median OS with acceptable toxicity in heavily pretreated colorectal cancer patients.