Background: Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of Clostidium difficile infection (CDI) due to use of cytotoxic chemotherapy, broad-spectrum antibiotics, and sustained neutropenia. Because of the immunocompromised nature of these patients, the prevalence rates of CDI in HSCT recipients are high. In this study we evaluate the impact of CDI on in-hospital outcomes. Methods: We included all patients with a prior diagnosis or a procedure code for HSCT using ICD-10 codes from National Inpatient Sample. We excluded patients admitted for less than 14 days to exclude admissions for elective chemotherapy or catheter placement. Patients were stratified into two groups based on the presence of CDI. Information was collected regarding patient demographics, Charlson comorbidities, underlying hematologic disease, resource utilization (LOS and total hospitalization charges), and outcomes. The outcomes included sepsis, shock, acute kidney injury, ICU admission, and in-hospital mortality. The association between CDI and outcomes was studied using multivariate analysis. Results: 62,415 patients were included in the study. Of them, 5,275 (8.5%) patients developed CDI. The majority of the patients with CDI were White (70.4%), men (57.1%), and aged between 45-64 years (52.5%). Patients with CDI had a higher incidence of sepsis (21.1% vs. 16.5%), shock (8.1% vs. 5.8%), AKI (23.8% vs. 19.4%), ICU admission (9.6% vs. 7.6%) and in-hospital mortality (5.8% vs. 4%). After adjusting for confounding factors, CDI was associated with a 32% higher odds of in-hospital mortality (aOR-1.32, 95% CI-1.01-1.74, p-0.046). CDI was also associated with 26% higher odds of developing shock (aOR-1.26, 95% CI-1.01-1.72, p-0.013) and 27% higher odds of developing AKI (aOR-1.27, 95% CI-1.09-1.49,p-0.002). No statistically significant difference was noted in the risk of ICU admission between the two groups. Patients with CDI had a longer length of stay (29.5 days vs. 24.8 days, p < 0.001) and higher hospitalization charges ($400,017 vs. $508,090, p < 0.001). Conclusions: Our study suggested a relationship between CDI and worse outcomes in HSCT recipients. Physicians should be aware of this association and promptly recognize and initiate treatment in these patients to improve outcomes.