Background: Chimeric Antigen Receptor T-cell (CAR-T) therapy, developed to address malignancies evading the immune system, has shown remarkable efficacy. However, its impact on infectious complications, particularly Clostridioides difficile infection, lacks real-world evidence. Our study aims to fill this knowledge gap by exploring prevalence, mortality rates, associated risk factors, and outcomes of C. difficile infections in CAR-T therapy patients. Methods: This retrospective analysis utilized National Inpatient Sample (NIS) data (2017-2019). We applied ICD-10 CM codes to identify CAR T therapy-related hospitalizations and Clostridioides difficile cases. Outcomes of interest included in-hospital mortality, length of hospitalization, total charges, and complications, associations, and interventions. Statistical analyses involved univariate and multivariate assessments, incorporating potential confounders such as age, gender, and Charlson Comorbidity Index score. Proportions and continuous variables were compared using appropriate tests with a significance level of P < 0.05. We conducted our statistical analysis using STATA Version 17 (College Station, TX: Stata Corp LLC). Results: We identified 685 inpatient cases of CAR-T therapy, among which 33 developed C. difficile infection, indicating an incidence of 4.8%. Mortality in the C. difficile group was 18.2%, significantly higher than the 2.8% in the non-C. difficile group (adjusted odds ratio: 7.67, 95% CI: 2.30 to 25.62, P<0.01). The mean length of stay for C. difficile cases was 30.9 days, compared to 19.1 days without C. difficile (coefficient: 11.01 days, 95% CI: 3.63 to 18.40, P<0.01). Total hospital charges were higher in the C. difficile group ($1,148,749) than the non-C. difficile group ($862,724), but not statistically significant (coefficient: $252,066, 95% CI: -78,332 to 582,464, P=0.134). Risks and outcomes associated with C