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 1 year, 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.