Our previous study showed that perinatal exposure to interleukin-1beta (IL-1beta), an inflammatory cytokine, induces acute injury to developing white matter in the neonatal rat brain, and alpha-phenyl-n-tert-butyl-nitrone (PBN), a free radical scavenger and antioxidant, protects against IL-1beta-induced acute brain injury. The objective of the present study was to further examine whether perinatal exposure to IL-1beta resulted in persistent brain damage and neurological disabilities, and whether PBN offers lasting protection. Intracerebral injection of IL-1beta (1 microg/kg) was performed in postnatal day 5 (P5) Sprague-Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after IL-1beta injection. Perinatal IL-1beta exposure significantly affected neurobehavioral functions in juvenile rats. Although some neurobehavioral deficits such as performance in negative geotaxis, cliff avoidance, beam walking, and locomotion were spontaneously reversible, sustained deficits such as poor performance in the vibrissa-elicited forelimb-placing test, the pole test, the passive avoidance task, and the elevated plus-maze task were still observable at P21. Perinatal IL-1beta exposure resulted in persistent brain damage including enlargement of ventricles, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, axonal and dendritic injury, and loss of hippocampal CA1 neurons and tyrosine hydroxylase positive neurons in the substantia nigra and ventral tegmental areas of the rat brain. Treatments with PBN provided lasting protection against the IL-1beta-induced brain injury and improved the associated neurological dysfunctions in juvenile rats, suggesting that prompt treatments for brain injury induced by perinatal infection/inflammation might have important long-term consequences.