The temporal and spatial expression of three immediate early genes was investigated at the level of both mRNA and protein in the brains of rats undergoing ethanol withdrawal. Animals were made dependent by chronic vapor inhalation. All animals showed behavioral signs of withdrawal between 8 and 17 h after removal from ethanol vapor. A large, transient increase in the expression of whole brain c-fos, c-jun, and zif/268 mRNA was observed 12 h after withdrawal, and expression of their protein products was detected 15 to 24 h after withdrawal. Spatial variation in the expression of each protein was detected. All three proteins were present in the cerebral cortex, the olfactory bulb, the inferior colliculus, the granular cell layer of the cerebellum, and in the brain stem, but only C-JUN and ZIF/268 were detected in the hippocampus of animals undergoing withdrawal without overt seizures. C-FOS was detected in the hippocampus only in animals with overt seizures. These data reveal a complex pattern of immediate early gene expression during ethanol withdrawal, which may be associated with changes in neuronal plasticity and/or cell repair.