Organophosphate (OP) pesticides are commonly known for their neurotoxicity. In the current experiments, two OPs used agriculturally, chlorpyrifos and dimethoate, were separately adminis- tered with centrally acting caffeine that is known to affect the pharmacological action of other substances. The aim of this study was to determine whether the combination of OP and caffeine may influence their neurotoxic potential. For this purpose, some neurobehavioral effects of this concomitant exposure were assessed in adult Swiss mice. All substances were given intra- peritoneally (i.p.) as single injections. In the passive avoidance task, chlorpyrifos (100 mg/kg) administered together with caffeine (40 mg/kg) significantly impaired acquisition. In the rota-rod test, the addition of caffeine at doses of 20 and 40 mg/kg, induced motor coordination impairment in chlorpyrifos (100 mg/kg)-treated mice. Neurobehavioral impairments were not observed for caffeine, chlorpyrifos and dimethoate (50 mg/kg) given separately as well as for the combina- tion of dimethoate and caffeine. Chlorpyrifos (100 mg/kg) alone and in combination with caffeine (40 mg/kg) significantly reduced acetylcholinesterase (AChE) activity. The current study shows that concomitant exposure to caffeine and chlorpyrifos can cause neurotoxic effects in mice despite the absence of these effects when caffeine and chlorpyrifos are administered alone. How- ever, the possible mechanisms involved need further investigations.