The developing nervous system is preferentially vulnerable to lead exposure with alterations in neuronal and glial cells of the brain. Chronic exposure to lead (Pb2+) causes deficits of learning and memory in children and spatial learning deficits in developing rats. Brn-3a is a member of the Pit-Oct-Unc (POU) family of transcription factors that is expressed predominantly in neuronal cells. It exists in two forms, with the long form containing 84 amino acids at the N-terminus that are lacking in the short form. The N-terminal domain unique to the long form induces expression of the Bcl-2 gene and protects neuronal cells against apoptosis whereas the C-terminal POU domain common to both forms is sufficient for activating a number of other neuronally expressed genes and stimulating neuronal process outgrowth. We examined Brn-3a protein and RNA expression in rat brain following low-level lead exposure during development and subsequent effects on spatial learning and memory. Two groups of rats were investigated: a control group and a lead-exposed group (0.2% lead acetate in the drinking water of the dam from gestational day 15 to postnatal day 21). Levels of Brn-3a were measured in rat cortex, hippocampus and cerebellum by immunohistochemistry and in situ hybridization, both protein and mRNA levels were reduced in lead-exposed group (p < 0.05). In Morris water maze, we found spatial learning deficits in rats of lead-exposed group (p < 0.05). These data suggest that the alteration of Brn-3a may play a key role in the mechanisms underlying lead neurotoxicity.