Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m25-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7–39%). Nausea and vomiting presented in two patients (8%; 95% CI 1–25%). The response rate of 26 patients can be summarized as follows: partial remission:n=7 (27%; 95% CI 12–48%); stable disease:n=9 (35%; 95% CI 17–56%) and progressive disease:n=10 (38%; 95% CI 20–59%). The median progression-free survival (n=26) was 5.8 months (range 3–13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2–24) and counted from the start of first-line treatment (n=26) was 23 months (range 10–66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.