To dissect gene expression subgroups of FOLFOX resistance colorectal cancer(CRC) and predict FOLFOX response, gene expression data of 83 stage IV CRC tumor samples (FOLFOX responder  = 42, non-responder  = 41) are used to develop a novel iterative supervised learning method IML. IML identified two mutually exclusive subgroups of CRC patients that rely on different DNA damage repair proteins and resist FOLFOX. IML was validated in two validation sets (HR = 2.6, Value = 0.02; HR = 2.36, value = 0.02). A subgroup of mesenchymal subtype patients benefit from FOLFOX. Different subgroups of FOLFOX nonresponders may need to be treated differently.