Standard treatment for periprosthetic joint infection (PJI) involves 2-stage exchange with placement of an antibiotic-impregnated cement spacer (ACS). Conflicting evidence exists on the role of ACS in development of acute kidney injury (AKI) after first-stage surgery. In this randomized clinical trial, we aimed to compare the incidence of AKI between the first-stage of a planned 2-stage exchange vs 1-stage exchange. This study design isolates the effect of the ACS in otherwise identical treatment groups. The primary outcome variable was AKI, defined as a creatinine ≥1.5 times baseline or an increase of ≥0.3 mg/dL. Risk factors for AKI were evaluated using bivariate statistical tests and multivariable logistic regression. Patients who underwent the first stage of a planned 2-stage exchange were significantly more likely to develop AKI compared with the 1-stage exchange group (15 [22.7%] vs 4 [6.6%], P= .011). On multivariable regression analysis, ACS placement (odds ratio 7.48, 95% confidence limit 1.77-31.56) and chronic kidney disease (odds ratio 3.84, 95% confidence limit 1.22-12.08) were independent risk factors for AKI. Our study provides evidence that high-dose antibiotic cement spacers for treatment of PJI are an independent risk factor for AKI. Therefore, efforts to minimize nephrotoxicity should be employed in revision for PJI when possible.