Vitamin E has been shown to affect cytokine production. However, individual response to vitamin E supplementation varies. Previous studies indicate that cytokine production is heritable and common single nucleotide polymorphisms (SNP) may explain differences in cytokine production between individuals. We hypothesize that the differential response to the immunomodulatory actions of vitamin E reflects genetic differences among individuals, including SNP at cytokine genes that modulate cytokine production. We used data from a double-blind, placebo-controlled 1-y vitamin E (182 mg d,l-alpha-tocopherol) intervention study in elderly men and women (mean age 83 y) to test this hypothesis (vitamin E, n = 47; placebo, n = 63). We found that the effect of vitamin E on tumor necrosis factor (TNF)-alpha production in whole blood stimulated for 24 h with lipopolysaccharide (1.0 mg/L) is dependent on TNFalpha -308G > A. Participants with the A/A and A/G genotypes at TNFalpha -308G > A who were treated with vitamin E had lower TNFalpha production than those with the A allele treated with placebo. These observations suggest that individual immune responses to vitamin E supplementation are in part mediated by genetic factors. Because the A allele at TNFalpha has been previously associated with higher TNFalpha levels in whole blood and isolated immune cells, our observations suggest that the antiinflammatory effect of vitamin E is specific to those genetically predisposed to higher inflammation. Further studies are needed to determine the biological mechanism driving the interaction between vitamin E treatment and TNFalpha -308G > A and its implications for disease resistance.