Background: Cell cycle progression and arrest of renal tubular cells after acute injury is a reactive process of renal regeneration. The p16<sup>INK4a</sup>/p19<sup>ARF</sup> (alternative reading frame) locus encodes two proteins involved in cell cycle regulation. We investigated the transcriptional regulation and tissue distribution of p19<sup>ARF</sup> in ischemic acute renal failure (ARF). Methods: We examined the time course and immunohistochemistry of p19<sup>ARF</sup> in rat kidneys following the induction of ischemic ARF. We also examined the effect of p19<sup>ARF</sup> overexpression on p53 levels and cell cycle progression in MDCK cells. Results: The protein expression of p19<sup>ARF</sup> strongly increased 72 h after the ischemia. Immunohistochemical studies showed that the renal tubular cells in the outer medulla expressed p19<sup>ARF</sup> protein 72 h after ischemic injury. The time course of E2F1 induction was observed at 6–24 h, and it was found to precede p19<sup>ARF</sup> expression. In MDCK cells, the overexpression of E2F1 increased promoter activity and the protein level of p19<sup>ARF</sup> and induced apoptosis. Transfection of the p19<sup>ARF</sup> expression vector caused an increase in p53 protein, cell cycle arrest and apoptosis. Conclusions: These data support the hypothesis that the E2F1-p19<sup>ARF</sup>-p53 pathway forms a negative feedback loop to regulate the cell cycle of renal tubular cells in the ischemic ARF.