Phenserine ((-)-N-phenylcarbamoyl eseroline), a carbamate analog of physostigmine (Phy), is a long-acting inhibitor of cholinesterase. We have assessed the potential clinical value of phenserine for cholinomimetic therapy of cognitive impairments associated with aging and Alzheimer's disease by evaluating its duration of in vivo activity against rat plasma acetylcholinesterase (AChE) and its effect on attenuating a scopolamine-induced impairment in learning performance of young rats in a shock-motivated 14-unit T-maze. Phenserine achieved maximum AChE inhibition of 73.5% at 5 min and maintained a high and relatively constant inhibition for more than 8 h. For analysis of effects on learning performance, 69, 3-month-old male Fischer-344 rats were pretrained in a straight runway to avoid electric footshock. On the following day, each animal received 15 trials in the 14-unit T-maze. Sixty minutes prior to the maze training, each rat received the first IP injection of either vehicle (Tween 80, ethanol and 0.9% NaCl) or phenserine at 1.5, 3.0, 4.0, 5.0, 7.5, or 10.0 mg/kg. Then 30 min prior to the training, each animal received a second IP injection of either 0.9% NaCl or scopolamine hydrochloride (0.75 mg/kg; SCOP). Compared to the vehicle-SCOP group, all but the 7.5 mg/kg dose of phenserine significantly ameliorated error performance, runtime, shock frequency and shock duration in SCOP-treated rats at the final block of three trials. Appearing to have a long effect and a wide therapeutic window, phenserine deserves further study as a cognitive enhancer.