The purpose of this study was to determine whether cimetidine exerts a protective effect against toxicity of organophosphate pesticides requiring metabolic activation in mice and rats. In both species, pretreatment with cimetidine (75 mg/kg/ip) 30 min prior to methylparathion (MP) reduced lethality and delayed the onset of cholinergic signs of toxicity. In contrast when cimetidine was administered simultaneously with MP to mice, neither MP‐induced lethality nor cholinergic signs of toxicity were altered. Moreover, cimetidine pretreatment failed to decrease parathion‐induced toxicity in mice.