This study compared the effect of vitamin E on the course of influenza infection with that of other antioxidants. (In a previous study we showed that short-term vitamin E supplementation significantly decreased pulmonary viral titer in influenza-infected old mice). Eighteen-month-old C57BL/6NCrlBR mice were fed one of the following semisynthetic diets for 6 months: control, vitamin E supplemented, glutathione supplemented, vitamin E and glutathione supplemented, melatonin supplemented, or strawberry extract supplemented. After influenza virus challenge, mice fed vitamin E-supplemented diet had significantly lower pulmonary viral titers compared to those fed the control diet (10(2.6) vs 10(4.0), p < .05) and were able to maintain their body weight after infection (1.8+/-0.9 g weight loss/5 days postinfection in vitamin E group vs 6.8+/-1.4 g weight loss/5 days postinfection in control group, p < .05). Other antioxidants did not have a significant effect on viral titer or weight loss. There was a significant inverse correlation of weight loss with food intake (r = -.96, p < .01), indicating that the observed weight changes were mainly due to decreased food intake. Pulmonary interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha levels increased significantly postinfection. The vitamin E group had lower lung IL-6 and TNF-alpha levels following infection compared to the control group. In addition, there was a significant positive correlation between weight loss and lung IL-6 (r = .77, p < .01) and TNF-alpha (r = .68, p < .01) levels. Because IL-6 and TNF-alpha have been shown to contribute to the anorexic effect of infectious agents, the prevention of weight loss by vitamin E might be due to its reduced production of IL-6 and TNF-alpha following infection. Thus, among the antioxidants tested, only vitamin E was effective in reducing pulmonary viral titers and preventing an influenza-mediated decrease in food intake and weight loss. Other dietary antioxidant supplementations that reduced one or more measures of oxidative stress (4-hydroxynonenal, malondialdehyde, and hydrogen peroxide) did not have an effect on viral titer, which suggests that, in addition to its antioxidant activity, other mechanisms might be involved in vitamin E's beneficial effect on lowering viral titer and preventing weight loss.