The aim of this study was to evaluate the protective effect of different doses of diphenhydramin against acute toxicosiswith Levamisole. The Mechanism of levamisole induced acute toxicity and that of protective effect of diphenhydramin againstLevamisole toxicosis also examined on the level of cholinesterase (ChE) activity. Subcutanous injection of 100mg/kglevamisole in male mice with induced cholinergic over stimulation and death in 100% of animals. The Toxicosis was notrelated to the significantly decreased in plasma, red blood cells and brain ChE activity. Injection low dose of diphenhydramin2.5mg/kg S.C. 15 min before levamisole produced protective effect against acute toxicity with levamisole. Significantlydecreased the severity of toxicosis and increased survival rates to 100%. Diphenhydramin at low dose alone or with acute doseof levamisole did not Produced Significantly inhibition in ChE activity.The data suggested that the toxic effect of Levamisolewas not related to inhibition of ChE. The low dose of diphenhydramin protected mice from Levamisole toxicity. The antidoataleffect of diphenhydramin not at the level of protection from ChE inhibition. There was no adverse interaction between twodrugs.