The efficacies of a number of drug treatment combinations in protecting guinea pigs against the lethal and incapacitating effects of soman (and sarin) have been determined. Incapacitation was studied using a swimming test which is a measure of gross motor performance. The drug combinations employed had no effect on the swimming performance of unpoisoned animals. Pyridostigmine pretreatment supported by postpoisoning therapy with atropine, pralidoxime mesylate (P2S), and diazepam protected guinea pigs against the lethal actions of soman and sarin, but the treatment was less effective in protecting against the agent-induced decrements in swimming performance. Replacing pyridostigmine (a quaternary carbamate) by physostigmine (which readily enters the CNS) and introducing aprophen (an anti-cholinergic drug with a range of pharmacological actions) improved the protection achieved against both lethality and incapacitation. When the postpoisoning therapy was omitted, pretreatment with physostigmine and aprophen (or some other anti-cholinergic drug) gave significant levels of protection against both soman- and sarin-induced lethality and incapacitation. It is concluded that a number of different pharmacological actions are required to antagonize nerve agent-induced incapacitation and that they, and their relative importance, remain to be identified.