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Acute kidney injury is a common and severe complication of critical illness and cardiac surgery. Despite significant attempts at developing treatments, therapeutic advances to attenuate acute kidney injury and expedite recovery have largely failed.Identifying genetic loci associated with increased risk of acute kidney injury may reveal novel pathways for therapeutic development.We conducted an exploratory genome-wide association study to identify single-nucleotide polymorphisms associated with genetic susceptibility to in-hospital acute kidney injury.We genotyped 609,508 single-nucleotide polymorphisms and performed genotype imputation in 760 acute kidney injury cases and 669 controls. We then evaluated polymorphisms that showed the strongest association with acute kidney injury in a replication patient population containing 206 cases with 1,406 controls. We observed an association between acute kidney injury and four single-nucleotide polymorphisms at two independent loci on metaanalysis of discovery and replication populations. These include rs62341639 (metaanalysis P = 2.48 × 10−7; odds ratio [OR], 0.64; 95% confidence interval [CI], 0.55–0.76) and rs62341657 (P = 3.26 × 10−7; OR, 0.65; 95% CI, 0.55–0.76) on chromosome 4 near APOL1-regulator IRF2, and rs9617814 (metaanalysis P = 3.81 × 10−6; OR, 0.70; 95% CI, 0.60–0.81) and rs10854554 (P = 6.53 × 10−7; OR, 0.67; 95% CI, 0.57–0.79) on chromosome 22 near acute kidney injury-related gene TBX1.Our findings reveal two genetic loci that are associated with acute kidney injury. Additional studies should be conducted to functionally evaluate these loci and to identify other common genetic variants contributing to acute kidney injury.