<p>Acute kidney injury (AKI) is a common and clinically important complication in hospitalized adults receiving nephrotoxic therapies. This study aimed to compare the incidence, timing, and severity of creatinine-defined AKI in patients receiving vancomycin plus Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) inhibitor only vs vancomycin plus NKCC inhibitor plus piperacillin–tazobactam. A retrospective observational cohort study was performed using MIMIC-IV version 3.1. Adult hospital admissions with qualifying exposure within the first 48 h of hospitalization were included. Group A comprised patients receiving vancomycin plus NKCC inhibitor only, and group B comprised patients receiving vancomycin plus NKCC inhibitor plus piperacillin–tazobactam. AKI was defined using KDIGO serum creatinine criteria. Multivariable logistic regression was used to evaluate any AKI, early AKI, and stage 2–3 AKI after adjustment for baseline renal risk and illness severity. The final analytic cohort included 5204 hospitalizations, with 4632 in group A and 572 in group B. Any AKI occurred in 28.0% of group A and 29.2% of group B, early AKI in 23.1% and 24.8%, and stage 2–3 AKI in 9.3% and 12.8%, respectively. Median time to AKI was similar at approximately 21.7 h in both groups. After adjustment, group B was not independently associated with any AKI (OR = 1.034), early AKI (OR = 1.115), or stage 2–3 AKI (OR = 1.107). Higher baseline creatinine, chronic kidney disease, mechanical ventilation, hypotension, liver disease, and sepsis were stronger predictors of renal outcomes. In hospitalized adults already receiving vancomycin and NKCC inhibitors, addition of piperacillin–tazobactam was not independently associated with higher odds of creatinine-defined AKI after adjustment. The observed crude excess in severe AKI and worse hospital outcomes appeared to reflect a sicker clinical phenotype rather than a clear independent nephrotoxic effect.</p>