Neuroimaging and post-mortem studies indicate that chronic alcohol use induces global changes in brain morphology, such as cortical and subcortical atrophy. Recent studies have shown that frontal lobe structures are specifically susceptible to alcohol-related brain damage and shrinkage in this area is largely due to a loss of white matter. This may explain the high incidence of cognitive dysfunction observed in alcoholics. Using a proteomics-based approach, changes in protein expression in the dorsolateral prefrontal region (BA9) white matter were identified in human alcoholic brains. Protein extracts from the BA9 white matter of 25 human brains (10 controls; eight uncomplicated alcoholics; six alcoholics complicated with hepatic cirrhosis; one reformed alcoholic) were separated using two-dimensional gel electrophoresis. Overall, changes in the relative expression of 60 proteins were identified (P<0.05, ANOVA) in the alcoholic BA9 white matter. In total, 18 protein spots have been identified using MALDI-TOF; including hNP22, alpha-internexin, transketolase, creatine kinase chain B, ubiquitin carboxy-terminal hydrolase L1 and glyceraldehyde-3-phosphate dehydrogenase. Several of these proteins have been previously implicated in alcohol-related disorders and brain damage. By identifying changes in protein expression in this region from alcoholics, hypotheses may draw upon more mechanistic explanations as to how chronic ethanol consumption causes white matter damage.