Ethanol (20% w/v) given to female, C57BL/6 mice in their drinking water suppresses natural killer (NK) and lymphokine activated killer cell cytolytic activity in mixed splenocytes and in splenocytes highly enriched for NK cells. The present study examined the effects of ethanol consumption on rIL2-induced proliferation of enriched NK cells. Mice were given 20% w/v ethanol in the drinking water for 2 weeks. Splenic NK cells were harvested and enriched up to 88% based on surface expression of NK1.1. The enriched NK cells were cultured in the presence of 1000 IU/ml (20 pg/ml) murine recombinant interleukin 2 (rIL2). There were fewer cells (p < 0.02) from ethanol-consuming mice compared to cells from water-drinking control mice after incubation with IL2 at 2, 4, and 6 days of culture. Ethanol consumption was associated with significantly lower [3H]thymidine uptake (p < 0.05). Ethanol consumption did not affect apoptosis or intracellular levels of interferon-gamma, tumor necrosis factor-alpha, or granulocyte macrophage colony-stimulating factor in NK cells. Ethanol consumption did not affect the expression of c-myc mRNA in NK cells that were cultured for 10 min or 4, 8, and 18 hr in rIL2. Suppression of IL2-induced NK cell proliferation is associated with ethanol consumption, and suppression is not due to altered IL2 receptor expression, increased apoptosis, intracellular cytokine levels, or c-myc expression.