The elderly suffer a decline in immune function that increases their vulnerability to infections. Because antioxidants improve some age-related deficits in immune and cognitive function, our goal was to determine whether dietary alpha-tocopherol (alpha-T) and selenium inhibit LPS-induced sickness behavior in aged mice. Male BALB/c mice were fed modified AIN93-M diets that were low, adequate, or high in both alpha-T (10, 75, or 500 mg/kg) and selenium (0.05, 0.15, or 2 mg/kg) from 18 to 21 mo of age. Sickness was quantified by measuring time in social exploration of a novel juvenile conspecific. The lipopolysaccharide treatment reduced social exploration by 74% at 2 h, regardless of diet. By 4 h, aged mice fed the low diet were 88% less social, whereas mice fed the adequate and high diets displayed only approximately 40% reductions due to LPS treatment. Mice fed the low diet had greater LPS-induced weight loss than mice fed the high diet. Plasma alpha-T concentration and glutathione peroxidase (GPX) activity increased with each increment in alpha-T and selenium 24 h post-LPS treatment. Brain alpha-T concentration and GPX activity were lower in mice fed the low diet than in those fed the adequate or high diet. Regardless of diet, interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)alpha mRNA levels were elevated by LPS approximately 3-fold in cortex, cerebellum, striatum, and hippocampus. Thus, antioxidants inhibit sickness behavior independently of IL-6, IL-1beta, and TNFalpha mRNA levels 2 h post-LPS in the brain regions analyzed. Taken together, these findings suggest that adequate intake of dietary alpha-T and selenium may help promote recovery from gram-negative bacterial infection in the aged.