Collagenous enteritis is an uncommon small intestinal injury pattern with unclear pathogenesis. While it has been speculated that collagenous enteritis represents a form of refractory celiac disease, recent clinical studies suggest a potential link to exposure to the antihypertensive medication olmesartan. Here we hypothesized that the pathogenesis of collagenous enteritis involves both genetic and environmental factors. All subjects with biopsy-proven collagenous enteritis diagnosed between 2002 and 2015 were identified from 2 tertiary care medical centers. Human leukocyte antigen (HLA)-DQ genotyping was performed by polymerase chain reaction on archived tissue. Celiac disease serology, past medical history, medications, smoking history, demographics, histology, clinical management, and follow-up were recorded. A total of 32 subjects were included. In contrast to celiac disease, subjects with collagenous enteritis were mostly elderly (median age at diagnosis, 69 y; range, 33 to 84 y). Seventy percent of collagenous enteritis subjects harbored celiac disease susceptibility alleles HLA-DQ2/DQ8; however, only 1 subject had elevated serum levels of celiac disease-associated autoantibodies while on a gluten-containing diet. Furthermore, 56% of subjects were taking nonsteroidal anti-inflammatory drugs, 36% proton-pump inhibitors, 28% statins, and 32% olmesartan at the time of diagnosis. Discontinuation of olmesartan and treatments with steroids and/or gluten-free diet resulted in symptomatic and histologic improvement. Neither lymphoma nor collagenous enteritis-related death was seen in this cohort. Therefore, while collagenous enteritis shares similar HLA genotypes with celiac disease, the difference in demographics, the lack of celiac disease-associated autoantibodies, and potential link to medications as environmental triggers suggest the 2 entities are likely distinct in pathogenesis.