INTRODUCTION: Studies suggest an association between colon ischemia (CI) and C. difficile-associated diarrhea (CDAD). It is unclear, however, if CI disease severity, attendant antibiotic use, or both are risk factors for CDAD. The aim of our study was to answer these questions. METHODS: A retrospective cohort study was performed on patients admitted to Montefiore Medical Center and Yale New Haven Hospital between 2005 and 2017 with a diagnosis of biopsy-proven CI. Patients who developed CDAD within 90 days of diagnosis of CI were identified. Various epidemiological factors were included (e.g., demographics, medical history, medication exposures, outcome, etc.). CDAD was defined by diarrhea and a positive C. difficile toxin assay. Patients with prior CDAD diagnosed within 90 days before admission for CI were excluded. Severity of CI was defined according to ACG Clinical Guideline recommendations. Bivariate analyses were performed to compare incidence of CDAD between groups with mild, moderate, and severe CI. Additionally, bivariate analyses were performed to compare epidemiological factors between cohorts with and without CDAD. RESULTS: Of 853 patients with biopsy-proven CI, 16 (1.9%) acquired CDAD within 90 days. There was a trend for those who developed CDAD to be older than those who did not (75 [64,82] vs 70 [61,80] years, respectively; P = 0.37; Table 1). Severity of CI was not significantly associated with incidence of CDAD (mild: 0%; moderate: 1.5%; severe: 2.1%; P = 0.63). Antibiotic use was more common in patients who developed CDAD than in those who did not (80% vs 69.3%), however, this finding was not statistically significant (P = 0.57; Table 1). Demographic data, ICU admission, length of stay, inpatient PPI use, and colectomy for CI were not significantly associated with CDAD development (Table 1). CONCLUSION: Typically, antibiotic use is strongly associated with CDAD but the similar incidence of CDAD between those who did and did not receive antibiotics in our cohort remains unexplained. One possible explanation is that the unique type of injury and healing of the colon wall in CI along with other factors play an important role independent of antibiotic use. The low CDAD incidence might reflect a compromised immune epithelial barrier, allowing more serologically-driven antibodies access to the bowel lumen, thereby minimizing CDAD development by (neutralizing) toxin A and B. Larger studies are needed to better understand the relationship between CDAD and CI.