Importance: Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Protein loading appears nephroprotective; thus, continuous hyperoncotic albumin infusion may impact AKI following high-risk cardiac surgery. Objective: To evaluate the effect of postoperative 20% albumin infusion compared with usual care on the occurrence of AKI in high-risk cardiac surgery patients. Design, Setting, and Participants: This was an investigator-initiated randomized multicenter open-label pragmatic clinical trial. Participants were stratified by site and estimated glomerular filtration rate (eGFR) above and below 60 mL/min/1.73 m2. The study was conducted at 7 cardiac centers in Australia and Italy between July 2019 and August 2024. Patients undergoing on-pump cardiac surgery with a preoperative eGFR of greater than 15 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 or undergoing a combined cardiac surgical procedure or major aortic surgery were included, excluding those who were in intensive care for longer than 6 hours following the index surgery, had a serum albumin level less than 20 g/L, were dialysis dependent, had a previous kidney transplant, were receiving extracorporeal life support or ventricular assist device, or had an objection to receiving albumin or blood products. Interventions: Participants were randomized 1:1 within 6 hours after surgery to receive a 300-mL infusion of 20% albumin over 15 hours or usual care, as per clinician discretion. All patients received volume resuscitation and hemodynamic treatment according to participating centers' protocols. Main Outcomes and Measures: The primary outcome was stage 1-3 AKI according to the creatinine-based Kidney Disease Improving Global Outcomes definition. The main secondary outcomes included major adverse kidney events and mortality at hospital discharge or day 28 following randomization. Results: The primary analysis included 307 patients randomized to the 20% albumin group and 304 to usual care. The mean (SD) age was 69 (10.8) years, and 281 patients (45.8%) had an eGFR less than 60 mL/min/1.73 m2. The median (IQR) European System for Cardiac Operative Risk Evaluation score-II was 3.23 (1.91-5.30). AKI occurred in 150 of 307 patients in the albumin group (48.9%) vs 132 of 304 in usual care (43.4%) (unadjusted relative risk, 1.13; 95% CI, 0.95-1.34; P = .18; strata-adjusted relative risk, 1.12; 95% CI, 1.04-1.21; P = .003). This effect was more pronounced in patients with an eGFR of <60 mL/min/1.73 m2 (adjusted relative risk, 1.14; 95% CI; 1.07-1.22; P < .001). There were more blood transfusions given in the albumin group (116 [37.8%] vs 91 [29.9%]; P = .04) but no other significant differences in secondary outcomes. Conclusions and Relevance: In this study of cardiac surgery patients at high risk of AKI, an infusion of 20% albumin increased the risk of AKI. These findings do not support the routine use of hyperoncotic albumin infusion in patients undergoing high-risk cardiac surgery. Trial Registration: Anzctr.org.au Identifier: ACTRN12619001355167.