Background: Cirrhosis is the result of chronic liver disease that causes scarring and dysfunction of the liver. The disease is a common concomitant condition resulting from sustained exposure to alcohol. Heavy alcohol use results in brain damage that is generally more severe in cirrhotic compared with noncirrhotic alcoholics. We examined, at the cellular level, gene expression in the frontal cortex of cirrhotic alcoholics. Methods: Gene expression profiles were compared between cirrhotic and noncirrhotic alcoholics using 47,000 element cDNA microarrays. Results: Widespread differences in transcriptome patterns were observed in cirrhotic compared with noncirrhotic alcoholics and these differences in gene expression accurately distinguished cirrhotic from noncirrhotic alcoholics. Functionally related groups of genes were identified that are involved in cell adhesion, mitochondrial function, synaptic transmission, apoptosis, and cell proliferation. Both astrocytes and neuronal cells were affected at the transcriptional level. The regulated genes are involved in neurite growth, neuronal cell adhesion, synaptic vesicle release, and postsynaptic neurotransmission. Conclusions: These changes in the transcriptome likely contribute to the more severe brain dysfunction in cirrhotic alcoholics.