Postoperative cognitive decline is a major clinical problem with high morbidity and mortality after surgery. Many studies have found that molecular hydrogen ( H-2) has significant neuroprotection against acute and chronic neurological injury by regulating inflammation and apoptosis. In this study, we hypothesized that H-2 treatment could ameliorate the development of cognitive impairment following surgery. Adult male rats were subjected to stabilized tibial fracture operation under anesthesia. Two percent of H-2 was inhaled for 3 h beginning at 1 h after surgery. Separate cohorts of rats were tested for cognitive function with fear conditioning and the Y-maze test, or euthanized to assess blood-brain barrier integrity, and systemic and hippocampal proinflammatory cytokine and caspase-3 activity. Surgery-challenged animals showed significant cognitive impairment evidenced by a decreased percentage of freezing time and an increased number of learning trials on days 1, 3, and 7 after operation, which were significantly improved by H-2 treatment. Furthermore, H2 treatment significantly ameliorated the increase in serum and hippocampal proinflammatory cytokines tumor necrosis factor-a, interleukin-1 beta, interleukin-6, and highmobility group protein 1 in surgery-challenged animals. Moreover, H-2 treatment markedly improved blood-brain barrier integrity and reduced caspase-3 activity in the hippocampus of surgery-challenged animals. These findings suggest that H-2 treatment could significantly mitigate surgery-induced cognitive impairment by regulating inflammation and apoptosis. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.