The aim of this study was to investigate the effect of treatment with creatine on the neuro and hepatotoxic effects of acute malathion exposure. Rats received malathion (150 mg/kg, i.p. injection) for two successive days either alone or combined with creatine at doses of 160, 360 or 720 mg/kg, orally. Serum acetylcholine esterase (AChE), butyryl cholinesterase (BuChE) and paraoxonase-1 (PON1) activities were determined in addition to comet assay. Malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) activity and nitric oxide (NO) were determined in brain and liver tissues. Serum BuChE, AChE and PON1 activities were inhibited after the administration of malathion. Malathion resulted in an increase in MDA, NO; a decrease in GSH level and SOD activity in both brain and liver tissues. Malathion also caused marked increase in DNA damage of peripheral blood lymphocytes. These effects of malathion were ameliortaed with the administration of creatine. Our data indicate that creatine protects against malathion neuro and hepatic adverse effects, most likely through direct antioxidant mechanism and up regulation of antioxidant defense systems.