Background <p>Discontinuation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARBs) is a common component of many nephrotoxin-associated acute kidney injury (NA-AKI) prevention strategies, though their intrinsic nephrotoxic potential has been increasingly challenged. We hypothesized that ACEI/ARBs would associate with increased overall AKI and stage 2/3 AKI in hospitalized adults receiving multiple nephrotoxins.</p> Methods <p>This retrospective cohort study included adult patients admitted to the University of Iowa Hospital for ≥ 3 days from 2014 to 2022. We compared patients receiving 2 nephrotoxins to patients receiving 3, with one being an ACEI/ARB. This allowed us to compare patients not counted as having a high nephrotoxin exposure to a group that would due to an additional ACEI/ARB. The primary outcome was AKI within 7 days of initial exposure. Secondary outcomes included stage 2/3 AKI and AKI occurring within 3 and 14 days of initial exposure. Generalized estimating equations with robust standard errors were used to estimate associations and incorporated inverse probability of treatment weighting (IPTW) based on 30 clinical covariates.</p> Results <p>The primary analysis included 15,438 patients exposed to two non-ACEI/ARB nephrotoxins, of which 1,106 (7.2%) also received an ACEI/ARB. Groups were well-matched after IPTW. Adjusted risk of AKI was 25% (95% CI 22–29%) in the ACEI/ARB group, and 20% (19–21%) in the comparator group (adjusted odds ratio 1.35, 95% CI 1.07–1.71). In contrast, ACEI/ARB exposure was not associated with increased risk of stage 2/3 AKI.</p> Conclusions <p>In a cohort of hospitalized patients receiving multiple nephrotoxic agents, ACEI/ARBs were associated with higher risks of AKI, but not higher rates of stage 2/3 AKI.</p>