Introduction Clostridium difficile infection (CDI) is a leading cause of hospital-acquired infection. Allogeneic hematopoietic stem cell transplant (aHSCT) recipients in the peri-transplant periods represent an especially vulnerable population due to chronic immunosuppression, prolonged hospital stays, and routine use of antibiotics (abx). Previous attempts to identify potential risk factors (RF) for CDI are inconsistent in the literature. Objectives Our study goals are to describe CDI incidence, associated risk factors, and CDI characteristics in our own aHSCT population. Study results will be utilized in designing future infection prevention strategies and to promote abx stewardship. Methods We retrospectively evaluated all aHSCT recipients between Jan 2011-May 2017 at Loyola University Cardinal Bernardin Cancer Center. Inclusion criteria included age >18, 1st aHSCT, and hematological malignancy. Both myeloablative and non-myeloablative conditioning regimens were included. Disease risk was defined by the ASBMT classification. RF for CDI included comorbid conditions, proton pump inhibitor (PPI) and abx use during the 1st 100 days after aHSCT, and development of acute (aGVHD) and chronic (cGVHD) graft vs host disease. Data pertaining to CDI classification was collected. aGVHD was graded based on the International BMT Registry System and cGVHD per the NIH consensus criteria. The peri-transplant period evaluated included 6 months prior to 2 years following aHSCT. Logistic regression analysis was performed to estimate adjusted odds ratios for factors associated with development of CDI. Results A total of 322 patients (pt) met our inclusion criteria, of which 89 (27.6%) developed CDI, 55 pts were classified as severe or severe-complicated per ACG criteria and 18 (20.2%) had recurrence within 60 days. Graft type consisted of 109 (33.9%) allogeneic matched related, 124 (38.5%) matched unrelated and 89 (27.6%) cord blood. This was a high risk group with most pts having either intermediate (60.1%) or high/very high (31.5%) disease risk. Infections were common, as 225 (69.9%) pts developing an infection during the 1st 100 days after aHSCT. In multivariable analysis, cord blood graft source (OR=1.99, 95% CI: 1.05-3.8, p = 0.036), PPI use (OR=2.02, 95% CI: 1.08-3.8 p = 0.028), and chronic GI GVHD (OR =5.86, 95% CI: 1.64-20.98, p = 0.018) were associated with increased odds of CDI. Lastly, female sex (OR=0.4, 95% CI: 0.25-0.78, p = 0.005) and GI tract infection (including hepatobiliary source) in first 100 days after HSCT (OR=0.41, 95% CI: 0.17-0.98 p=0.045) were associated with decreased odds of CDI. Of note, rates of II-IV aGVHD were low (N=49, 15%). Conclusion Our population had 27% incidence of CDI and we note that cord blood graft, PPI use, GI cGVHD were associated with increased risk for CDI. These findings may have important implications for the supportive care plans for aHSCT pts.