Background:  Neuropathological damage as a result of chronic alcohol abuse often results in the impairment of cognitive function. The damage is particularly marked in the frontal cortex. The 14‐3‐3 protein family consists of 7 proteins, β, γ, ε, ζ, η, θ, and σ, encoded by 7 distinct genes. They are highly conserved molecular chaperones with roles in the regulation of metabolism, signal transduction, cell‐cycle control, protein trafficking, and apoptosis. They may also play an important role in neurodegeneration in chronic alcoholism.Methods:  We used real‐time PCR to measure the expression of 14‐3‐3 mRNA transcripts in both the dorsolateral prefrontal cortex and motor cortex of human brains obtained at autopsy.Results:  We found significantly lower 14‐3‐3β, γ, and θ expression in both cortical areas of alcoholics, but no difference in 14‐3‐3η expression, and higher expression of 14‐3‐3σ in both areas. Levels of 14‐3‐3ζ and ε transcripts were significantly lower only in alcoholic motor cortex.Conclusions:  Altered 14‐3‐3 expression could contribute to synaptic dysfunction and altered neurotransmission in chronic alcohol misuse by human subjects.