Postoperative mental status changes are common after liver transplantation (LT). A clear cause of these mental status changes cannot be identified in a significant proportion of patients. In adult liver transplant recipients, our goals are to: (1) identify independent predictors for the development of post-LT mental status changes of unclear cause and (2) derive a practical formula to predict the risk for developing this complication by using simple clinical parameters. Eligible patients had documented mental status changes of at least 3 days' duration, occurring within 1 month of LT. Exclusion criteria were known structural brain disorders, major organ dysfunction, or metabolic causes of altered mentation. Age- and sex-matched controls were liver transplant recipients without post-LT neurological sequelae. Data were collected on preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were performed to detect factors predictive of the development of post-LT mental status of unclear cause. There were 40 cases and 40 controls. Independent predictors of mental status changes of unclear cause included alcoholic and metabolic liver diseases; pre-LT mechanical ventilation; Model for End-Stage Liver Disease (MELD) score greater than 15; and nonelective LT. Using these four preoperative factors, a simple predictive rule was developed. Risk for developing altered mental status of unclear cause after LT was 78% to 89% if all four predictors were present versus 0.8% to 2.4% if no predictors were present. In conclusion, alcoholic and metabolic liver diseases, pre-LT mechanical ventilation, MELD score greater than 15, and nonelective LT are independent predictive factors for post-LT altered mental status changes of unclear cause. A simple model can be used to calculate the risk for developing altered mental status post-LT.