Ethanol enhances expression of cell surface class I major histocompatibility complex (MHC) antigens in a variety of cell lines; up to an eightfold increase is observed in an embryonic cell lines. Treatment of mice with ethanol in vivo causes marked changes in both liver and spleen. In the livers of alcohol-treated mice, a significant increase in the level of class I MHC RNA occurs within 4-5 days of treatment. In both thymus and spleen, there is an acute cellular depletion. In the spleen, the T lymphocyte population is selectively spared. The finding of increased class I MHC expression in liver, with concomitant depletion of splenic lymphocytes, supports models in which autoimmune mechanisms may play a role in alcohol related diseases.