Background: Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (mCRC). In this non-randomized pilot study, we investigated the efficacy and safety of sequentially administered XELOX and XELIRI regimens or the reverse sequence in patients with advanced colorectal cancer. Patients and Methods: Entry criteria were histologically confirmed mCRC, ECOG performance status (PS) <= 2 and adequate bone marrow, renal and hepatic function. All patients consecutively received XELOX followed by XELIRI at disease progression or vice versa. Results: In multivariate analysis, independent prognostic factors with worse overall survival were: lower PS (p = 0.0001), multiple metastatic sites (p = 0.016) and high tumor grade. Higher serum levels of alkaline phosphatase and worse ECOG PS were associated with a shorter progression-free survival. Grade 3/4 mucositis, nausea/vomiting, grade 3/4 alopecia and grade 3 diarrhea were more frequent with XELIRI, whereas major toxicity events with XELOX were grade 3 neutropenia, thrombocytopenia and grade 2/3 neurotoxicity. Conclusion: Capecitabine appears to be an acceptable alternative to continuous-infusion fluorouracil (FU)/leucovorin (LV) in combination therapy and offers an effective, but more convenient alternative to continuous infusion FU/LV in the first-line treatment of patients with mCRC. Copyright (c) 2008 S. Karger AG, Basel.