Background: Elderly patients undergoing major surgery often develop cognitive dysfunction, and no optimum treatment exists for this postoperative complication. Ribonuclease, the counterpart of ribonucleic acid, has mostly been reported in terms of its use as a potential modality in anticancer therapy, and recent studies have demonstrated that ribonuclease can exert organ-protective effects in several pathological conditions. Our study also demonstrated that ribonuclease protects the liver against ischemia reperfusion injury. Nevertheless, it is unknown whether ribonuclease can attenuate the cognitive dysfunction that is induced by liver ischemia reperfusion. In this study, we aimed to evaluate the effect of ribonuclease on cognitive function after liver ischemia reperfusion. Methods: Aged mice underwent sham surgery or 60 min of hepatic ischemia reperfusion, vehicle or ribonuclease, which were administered subcutaneously. The primary observation endpoint was the Morris water maze; following 24 h, 3 days, and 7 days of reperfusion, the levels of serum and hippocampus proinflammatory cytokines were measured to reveal the underlying mechanism. Results: A probe test was conducted on day 3 and a reversal probe test was conducted on day 7 after surgery; the results demonstrated a reduction in cognitive function after liver ischemia reperfusion and that ribonuclease treatment attenuated cognitive impairment. The levels of serum and hippocampus proinflammatory cytokines (interleukin-6 and interleukin-1 beta) and extracellular ribonucleic acid were significantly increased at 24 h after reperfusion, but ribonuclease treatment markedly reduced the proinflammatory cytokine increase. Conclusion: The results of the study suggested that hepatic ischemia reperfusion leads to cognitive impairment in aged mice and an increase in inflammatory cytokine expression in both serum and the hippocampus; more importantly, ribonuclease showed protective effects against cognitive impairment through inhibiting the release of inflammatory cytokines. (C) 2017 Elsevier Masson SAS. All rights reserved.