Background: The aim of this study was to establish the protective effect of caffeic acid phenethyl ester (CAPE) against the ifosfamide (IFOS)-induced central neurotoxicity in rats and to determine the changes in oxidant-antioxidant status of brain tissue. Method: A total of 35 Wistar rats (aged 7-12 days) were used in the experiments. The study comprised of five groups. Control untreated rats (n = 7) belonged to group 1; group 2 was given intraperitoneal (IP) injection of CAPE alone (10 mmol/kg; n = 7); group 3 was treated with single IP injection of IFOS (500 mg/kg; n = 7); group 4 was treated for 2 days with IP administration of CAPE (10 mmol/kg) beginning from one day before single IP injection of IFOS (n = 7); and group 5 was treated with saline and 10% ethanol. At the 24th hour of IFOS treatment, brain tissues were removed for analysis. Results: The brain catalase activity was lower in IFOS group than the other groups (p < 0.05). The levels of malondialdehyde (MDA) and protein carbonyl content in brain tissue were higher in IFOS group than the control, CAPE, ethanol, and IFOS + CAPE groups (p < 0.05). There was no significant difference between MDA and protein carbonyl content of control, CAPE, ethanol, and IFOS + CAPE groups. Immunohistochemistry showed marked activation of caspase 3 in the IFOS group at 24 h after treatment. Conclusion: This study revealed that pretreatment with CAPE might protect brain tissue against IFOS-induced central neurotoxicity. CAPE could be an effective course of therapy to enhance therapeutic efficacy and to lessen IFOS toxicity in clinical chemotherapy.