Although the phenomenon that psychological stress influences disease onset and progression is well established, the mechanisms underlying stress-evoked compromise of immune function remain unspecified. To test the hypothesis that energetic shortages compromise immunity, we evaluated the effectiveness of pyruvate, a metabolic supplement, to prevent stress-evoked suppression of mitogen-stimulated splenocyte proliferation. Male C57BL/6 mice were subjected to 2h of restraint once daily for 14 days. Consistent with previous studies, mitogen-stimulated splenocyte proliferation was reduced after restraint; in contrast, mice that received pyruvate injections immediately following each episode of restraint did not reduce splenocyte proliferation. In addition, restraint-evoked corticosterone elevation did not habituate in animals treated with pyruvate, suggesting that glucocorticoids are not exclusively immunosuppressive. The ratio of pyruvate to lactate, an index of aerobic metabolism, was elevated in mice exposed to restraint suggesting that mice exposed to restraint were preferentially using aerobic metabolism and producing more ATP per unit of pyruvate than non-restrained mice. Furthermore, two of the effective doses of pyruvate (0.5 and 500.0mg/kg) altered glucose levels suggesting a metabolic function of the supplement. Although several different mechanisms could possibly mediate the changes in splenocyte proliferation, these results support the hypothesis that stress-evoked immunosuppression may be a function of metabolic energy shortages and can be prevented via pyruvate supplementation.