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Introduction: Angiotensin-converting enzyme inhibitors (ACEI) may have several pleiotropic effects, but the literature regarding a possible relationship between ACEI use and frailty is limited. We investigated whether ACEI use is associated with lower risk of frailty in a cohort of North American individuals. Methods: Data from the Osteoarthritis Initiative, a cohort study with 8years of follow-up including community-dwelling adults with knee osteoarthritis or at high risk for this condition, were analyzed. ACEI use was defined through self-reported information and confirmed by a trained interviewer. Frailty was defined using the Study of Osteoporotic Fracture (SOF) index as the presence of at least two of the following criteria: (1) weight loss ≥ 5% between baseline and any subsequent follow-up visit; (2) inability to do five chair stands; and (3) low energy level according to the SOF definition. A multivariable Poisson regression analysis was used to assess the association between ACEI use at baseline and incident frailty. The data were reported as relative risks (RRs) with their 95% confidence intervals (CIs). Results: The final sample consisted of 4295 adults (mean age 61.2years, females 58.1%). At baseline, 551 participants (12.8%) used ACEI. After adjusting for 15 potential confounders, the use of ACEI was associated with a lower risk of frailty (RR 0.72; 95% CI 0.53–0.99). The adjustment for the propensity score substantially confirmed these findings (RR 0.75; 95% CI 0.54–0.996). Conclusion: ACEI use may be associated with a reduced risk of frailty in individuals with/at risk of knee osteoarthritis, suggesting a potential role for ACI in the prevention of frailty. © 2019, Springer Nature Switzerland AG.