Persistent memory and learning disabilities may occur postoperatively and may be related to neurodegenerative processes. Epigenetic dysregulation has been implicated to abnormal brain function and neurodegenerative diseases. Some risk factors contributing to postoperative cognitive disorder (POCD) have been identified, including exposure to general anesthesia, hypotension, hypoxia, psychoactive drugs, hippocampal inflammation induced by the surgical intervention, etc. The current evidence supports these risk factors might induce epigenetic dysfunction in the brain. It is possible that epigenetic regulation might be the common downstream pathway of these risk factors, since the chromatin remodeling is necessary for the memory-associated gene transcription and expression. Here, we present our hypothesis that the epigenetic dysregulation might be a critical mechanism underlying POCD. Our hypothesis may lead to a new therapeutic strategy of epigenetic intervention for POCD. (C) 2012 Elsevier Ltd. All rights reserved.