Abstract: Background: Frailty is often more predictive of disease and mortality compared with chronological age. This study determined the impact of frailty on Clostridioides difficile infection (CDI) risk and outcomes in a national veteran population. Methods: This was a retrospective cohort study of CDI and control veteran inpatients and outpatients from fiscal year 2003 to 2018. Baseline frailty was presented as the Veterans Affairs (VA) Frailty Index. Propensity score--matched analyses were conducted to compare CDI risk, CDI health outcomes, and 1-year new-onset frailty-associated conditions. Results: A total of 11,451 CDI and 11,451 matched control patients were included. Baseline frailty conditions were more common among CDI patients, especially involuntary weight loss (6.0% vs 3.4%, P < .001) and anemia (24.6% vs 18.7%, P < .001). VA Frailty Index was significantly higher for CDI patients (0.13 vs 0.11, P = .019). Frail CDI patients were more likely to experience 30-day mortality (11.3% vs 1.1%, P < .001) and 60-day CDI recurrence (20.4% vs 16.3%, P < .001) compared with non-/prefrail CDI patients. At 1year, CDI patients were significantly more likely to be categorized as frail (19.6% vs 17.0%, P < .001). Conclusions: This study demonstrated the potential association between frailty and CDI risk and health outcomes, as well as new-onset frailty diagnoses in patients who develop CDI.