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Acute kidney injury (AKI) is a common clinical syndrome with few effective treatments. Though the kidney can regenerate after injury, the molecular mechanisms regulating this process remain poorly understood. Pax2 and Pax8 are DNA-binding transcription factors that are upregulated after kidney injury. However, their function during the response to AKI remains incompletely defined. In this report, we develop a model of ischemic AKI in female mice with mosaic nephrons comprised of both Pax2 and Pax8 mutant and wild-type proximal tubule cells with fixed lineages. Each population therefore experiences identical physiological and injury conditions in the same animal. In these female mice, we show that before injury the S1 and S2 segments of the proximal tubule are depleted of Pax-mutant cells, whereas mutant cells are preserved in the S3 segment. Retained S3 Pax-mutant cells develop a preconditioned phenotype that overlaps with gene expression signatures in AKI. In response to ischemic AKI, which most strongly damages the S3 proximal tubule, injury-resistant mutant S3 cells are more likely to proliferate. Pax-mutant cells then preferentially repopulate the S3 segment of the proximal tubule. Our results indicate that Pax2 and Pax8 are not required for regeneration of the S3 proximal tubule after ischemic AKI. Together, our findings indicate that Pax proteins play a critical role in determining the segment-specific proximal tubule gene expression patterns that dictate vulnerability to ischemic injury. NEW & NOTEWORTHY Acute kidney injury (AKI) is a common clinical syndrome with few effective treatments. In this report, we identify a novel and proximal tubule segment-specific role for the Pax family of transcription factors in the differential sensitivity of proximal tubule segments to ischemic AKI. These results may lead to new therapeutic targets for the prevention and treatment of AKI.