Scopolamine (SCP) is an anticholinergic drug used clinically for decades to treat motion sickness, as a surgical preanesthetic, and as a smooth muscle antispasmodic. It has also been used experimentally as a pretreatment and/or treatment adjunct to mitigate the toxic sequelae of organophosphorus (OP) nerve agent intoxication. SCP has been reported to increase survival, prevent or terminate seizures, and reduce morbidity from nerve agent intoxication in a number of animal models. The purpose of this study was to evaluate the effect of atropine dose, pyridostigmine bromide (PB) pretreatment, and oxime selection on the efficacy of SCP as an adjunctive treatment to enhance survival following lethal nerve agent exposure in guinea pigs. The results indicate that the use of an effective oxime and/or PB pretreatment was a critical factor in determining the efficacy of SCP. SCP can also reduce the dose of atropine required for survival against lethal nerve agent intoxication.