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.