The pathogenesis of necrotizing enterocolitis (NEC) remains poorly understood but is thought to be multifactorial. There are no specific recurring chromosomal abnormalities previously associated with NEC. We report 3 cases of intestinal necrosis associated with large chromosome 6 deletions. The first patient was found to have a 7.9-Mb deletion of chromosome 6 encompassing over 40 genes, arr[GRCh37] 6q25.3q26(155699183_163554531)×1. The second patient had a 19.5-Mb deletion of chromosome 6 generated by an unbalanced translocation with chromosome 18, 46,XY,der(6)t (6;18)(q25.1;p11.23), arr[GRCh37] 6q25.1q27(151639526_ 171115067)×1, 18p11.32p11.23(131700_7694199)×3, which included the whole 7.9-Mb region deleted in the first patient. The third patient was the younger sibling of the second patient with an identical derivative chromosome 6. The shared abnormal chromosome 6 region includes multiple genes of interest, particularly EZR. Mouse models have demonstrated that Ezr is expressed in microvillar epithelium and helps regulate cell-cell adhesion in the gut. We hypothesize that deletion of this shared region of 6q leads to gastrointestinal vulnerability which may predispose patients to intestinal necrosis.