In this study, we examined the ability of Pentoxifylline (PTX) to prevent sleep deprivation induced memory impairment probably through decreasing oxidative stress. Sleep deprivation was chronically induced 8 h/day for 6 weeks in rats using modified multiple platform model. Concurrently, PTX (100 mg/kg) was administered to animals on daily basis. After 6 weeks of treatment, behavioral studies were conducted to test the spatial learning and memory using the Radial Arm Water Maze. Additionally, the hippocampus was dissected; and levels/activities of antioxidant defense biomarkers glutathione reduced (GSH), glutathione oxidized (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), were assessed. The results show that chronic sleep deprivation impaired short- and long-term memories, which was prevented by chronic treatment with PTX. Additionally, PTX normalized sleep deprivation-induced reduction in the hippocampus GSH/GSSG ratio (P < 0.05), and activities of GPx, catalase, and SOD (P < 0.05). In conclusion, chronic sleep deprivation induces memory impairment, and treatment with PTX prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus. © 2013 Wiley Periodicals, Inc.