The effectiveness of physostigmine and atropine pretreatment against the lethal effects of sarin was studied in rats given lethal subcutaneous injections (130 micrograms/kg) of the organophosphate. Pretreatment of these animals with physostigmine 30 min prior to injection of sarin reduced mortality to 28% and when the drug coadministered with atropine only 4% of the animals died. The latter treatment also reduced significantly the extent and duration of symptoms due to sarin; however, atropine, pyridostigmine, and neostigmine injected alone did not protect animals against the lethal effects of sarin. Physostigmine caused only slight inhibition of cholinesterase in blood and skeletal muscle. Cholinesterase activity in blood and muscle of rats pretreated with physostigmine before sarin administration was significantly higher than in tissues from rats injected with sarin alone. In rats receiving sarin following pretreatment with physostigmine, twitch potentiation of extensor muscles and maintenance of tension during tetanic stimulation of the nerve recovered to near control levels. Muscle function recovered despite significant inhibition of cholinesterase. Effective protection against lethality by physostigmine could be related to protection of cerebral cholinesterase since inhibition of this enzyme by sarin was lowered significantly after pretreatment with physostigmine. Alternatively, physostigmine may also interact with the nicotinic acetylcholine receptor ion-channel complex directly.