Background: Colorectal cancer patients with unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and the lack of consensus on criteria for (un)resectability complicates the interpretation of published results. Methods: CAIRO5 is a multicenter, randomized, phase III clinical study. Colorectal cancer patients with initially unresectable liver-only metastases are eligible, and will not be selected for potential resectability to avoid selection bias. The unresectability status is prospectively assessed by a central panel consisting of at least one radiologist and three liver surgeons, and defined as no radical resection possible in one session with resection only. Tumors of included patients will be tested for RAS and BRAF (for stratification purpose) mutation status. Patients with RAS wild type tumors are treated with doublet chemotherapy (FOLFOX/FOLFIRI, choice of investigator) and randomized between the addition of either bevacizumab or panitumumab, patients with RAS mutant tumors are randomized between doublet chemotherapy (FOLFOX/FOLFIRI) or triple chemotherapy (FOLFOXIRI), both with bevacizumab. Resectability status will be re-evaluated every two months. The primary study endpoint is median progression-free survival. Secondary endpoints include the R0/1 resection rate, and median overall survival. Conclusion CAIRO5 is a prospective multicenter trial that investigates the optimal systemic therapy for patients with initially unresectable, liver-only colorectal cancer metastases. Discussion The unique aspects of CAIRO5 concern the prospective phase III randomized comparison of neoadjuvant treatment regimens in this population with the use of uniform and transparent criteria for unresectability by an expert panel. This CAIRO5 panel may contribute to a consensus on criteria for unresectability and to awareness of secondary resections in these patients. Clinical trial information: NCT02162563