Acute kidney injury (AKI) following exploratory laparotomy and temporary abdominal closure (TAC) is poorly understood but clinically significant. We hypothesized that the prevalence of AKI would be highest 96 h following TAC, early hypoxemia would predict AKI, and that AKI would be an independent predictor of mortality. We performed a retrospective analysis of 251 acute care surgery patients managed with TAC by negative pressure wound therapy (NPWT). Kidney Disease: Improving Global Outcomes AKI stages were assessed on admission, initial TAC, and following TAC at 48 h, 96 h, and 7 d. Multivariate regression was performed to identify risk factors for AKI and inpatient mortality. Fifty-seven percent of all patients developed AKI within 7 days of laparotomy (stage 1: 14%, 2: 21%, 3: 22%). The prevalence of AKI peaked 48 h following TAC, and stage correlated with inpatient mortality (stage 0: 7%, 1: 13%, 2: 19%, 3: 37%, P < 0.001). Overall mortality was 14%. Factors predictive of stage 2 or 3 AKI at 48 h included age >65 years (OR 2.6 [95% CI 1.4-4.9]), NPWT output >30 mL/h from first TAC to 48 h (2.0 [1.1-3.9]), and three parameters at initial laparotomy: mean arterial pressure <60 mm Hg (2.9 [1.0-8.5]), temperature <36°C (2.1 [1.1-3.8]), and anion gap >21 mEq/L (1.9 [1.0-3.7]). AKI was an independent predictor of inpatient mortality (5.5 [2.5-11.8]). AKI is common following TAC, reaches greatest prevalence 48 h after initial laparotomy, and is associated with increased mortality. NPWT fluid loss is a risk factor for AKI that is unique to TAC patients.