Groups of adult, male, Wistar rats were administered phenytoin (DPH) at 5, 12.5, 25, 50, or 75 mg/kg i.p. for 21 days. The learning and memory of these rats were assessed using the T-maze and passive avoidance tests. The plasma DPH levels, acetylcholine esterase (AChE) activity in different brain regions, and the levels of monoamines in the hippocampus were measured. The results indicate that DPH below the therapeutic plasma level did not significantly impair learning and memory. Correspondingly, no changes were noted in the brain 5-HT or AChE activity. However, DPH, at therapeutic plasma concentrations (i.e., 10.5 micrograms/ml in the dosage range of 50 and 75 mg/kg, respectively), significantly impaired learning and memory in rats. The impaired learning and memory functions were associated with increased 5-HT levels and decreased AChE activity in the hippocampus. With a dose of 75 mg/kg DPH, there was a reduction in the AChE activity in the striatum, in addition to hippocampus. It is conjectured that the neurochemical changes brought about by DPH at therapeutic plasma levels may account for the impairment of learning, memory, and cognitive functions in epilepsy.