Introduction: Little is known about the association between Clostridioides difficile infection (CDI) and celiac disease. The aim of the study is to describe the risk of CDI in patients with celiac disease and to describe the clinical outcomes in patients with celiac and CDI. Methods: We queried a commercial database (Explorys IncTM, Cleveland, OH, United States), and obtained an aggregate of electronic health record data from 26 major integrated United States healthcare systems comprising 360 hospitals in the United States from 2017 to 2022. Diagnoses were organized into the Systematized Nomenclature of Medicine Clinical Terms (SNOMED–CT) hierarchy. We compared the incidence of new CDI among patients with celiac disease versus those without celiac disease (controls). Univariate and multivariate analyses were performed on the data, and associations were reported as adjusted odds ratios (aOR) with 95% confidence intervals (CI). Results: We identified 90,060 patients with celiac disease and 25,807,720 controls. The incidence of new CDI was 1.31% (1,180) in celiac disease patients, and 0.35% (92,330) in controls, yielding an odds ratio (OR) of 3.69 (95% CI 3.49-3.91; P< 0.0001). Treatment and clinical outcomes were not significantly different. After controlling for common CDI risk factors, the multivariate analysis model uncovered that celiac patients were more likely to develop CDI OR: 1.34 (95% CI: 1.2-1.4, P < 0.0001) compared to controls (Table). Conclusion: In a large US population-based study, patients with celiac disease had a significantly higher incidence of CDI than controls. Clinical outcomes were similar between the groups. Clinicians should be vigilant and consider CDI in celiac patients with new or recurrent diarrhea. Table 1. - Demographics Celiac Patients (n=90,060) Control Patients (n=25,807,720) Age 18-65 years (%) 65,220 (72.4%) 18,331,970 (71%) Age >65 years (%) 24,840 (27.6%) 7,475,750 (29%) Female (%) 66,800 (74.2%) 13,219,060 (51.2%) Race: White (%) 73540 (81.7%) 14,072,590 (54.5%) Smoker (%) 15,120 (16.8%) 2,327,950 (9%) Alcohol abuse (%) 2,530 (2.8%) 552,010 (2.1%) Hypertension (%) 42,250 (46.9%) 8,063,140 (31.2%) Diabetes (%) 25,560 (28.4%) 3,446,990 (13.4%) Obesity (%) 26,170 (29.1%) 3,535,170 (13.7%) Clostridioides difficile infection management and clinical outcomes Developed Clostridioides difficile infection* 1,180 (1.31%) 92,330 (0.35%) Treated with metronidazole 820 (69%) 56,490 (61.1%) Treated with vancomycin 770 (65.2%) 55,270 (59%) Treated with fidaxomicin 70 (5.9%) 4,370 (4.7%) Colectomy** 10 (0.84%) 970 (1.05%) Multivariable model with Clostridioides difficile infection being the outcome Risk Factors Odds Ratio 95% CI; P-value Age ≥65 yr vs < 65yr 2.988 2.962-3.014; < 0.0001 Gender (female vs male) 1.194 1.184-1.204; < 0.0001 Race (White vs rest) 1.483 1.467-1.498; < 0.0001 Antibiotics 3.657 3.6-3.7; < 0.0001 Acid suppressive therapy*** 4.268 4.224-4.313; < 0.0001 Inflammatory bowel disease 6.031 5.93-6.13; < 0.0001 Celiac disease 1.342 1.284-1.403; < 0.0001 *1st occurrence of CDI after celiac diagnosis.**Colectomy performed within 60 days of CDI diagnosis (excluded patients with a history of IBD, ischemic colitis, and neoplasia of the colon).***Acid suppressive therapy includes prior use of proton pump inhibitors or H2 blockers