Ischemia/reperfusion injury (IRI) in liver and other organs is manifested by an injury phase followed by recovery and resolution. Control of cell growth and proliferation is essential for the recovery from the injury. Here we examined the expression of three related regulators of cell cycle progression: Spermidine/spermine N-acetyltransferase (SSAT), p21 (a cyclin-dependent kinase inhibitor) and stathmin in liver IRI. Mice were subjected to hepatic IRI and liver tissues were harvested at timed intervals. The expression of SSAT, p21, and stathmin was examined by Northern hybridization and immunoblot/immunolabeling, and SSAT enzymatic activity was assessed by polyamine measurement in liver tissues. The expression of SSAT, the rate limiting enzyme in polyamine catabolic pathway, increased by 5-fold at 6 hrs of IRI, and correlated with increased putrescine and decreased spermine and spermidine levels in the liver, consistent with increased SSAT enzymatic activity in IRI. The expression of p21, which is transactivated by p53, was undetectable in sham operated animals, but was heavily induced at 12 and 24 hours of reperfusion and declined to undetectable baseline levels at 72 hours of reperfusion. The interaction of polyamine pathway with p53/p21 pathway was shown in vitro, where activation of SSAT with polyamine analog or addition of putrescine to cultured hepatocytes induced the expression of p53 and p21 and decreased cell viability. The expression of stathmin, which is under the negative transcriptional regulation by p21 and controls cell proliferation and progression through mitosis, remained undetectable at six, 12 and 24 hours of reperfusion, and progressively and heavily induced at 48 and 72 hours of reperfusion. Double immunofluorescence labeling with antibodies against stathmin and PCNA, a marker of cell proliferation, demonstrated colocalization of stathmin and PCNA at 48 and 72 hours of reperfusion in hepatocytes, indicating the initiation of cell proliferation. The distinct and sequential upregulation of SSAT, p21 and stathmin, along with biochemical activation of polyamine catabolic pathway in IRI in vivo and demonstration of p53/p21 upregulation by SSAT and putrescine in vitro, points to the important role of regulators of cell growth and cell cycle progression in the pathophysiology and or recovery from injury in liver IRI. The data further suggest that SSAT may play a role in the initiation of injury whereas p21 and stathmin may be involved in the resolution and recovery of liver IRI.