Exercise stress is associated with an increased risk for URTI. We have shown that consumption of the soluble oat fiber, -glucan (OG) can offset the increased risk for infection and decreased macrophage ant-viral resistance following stressful exercise, however, the direct role of macrophages is unknown. This study examined the effect of macrophage depletion on the benefits of orally administered OG on susceptibility to infection (morbidity, symptom severity and mortality) following exercise stress. Clodronate (Ex-H₂O-CL₂MDP, Ex-OG-CL₂MDP, Con-H₂O-CL₂MDP, Con-OG-CL₂MDP) encapsulated liposomes were administered intra-nasally to deplete macrophages, PBS (Ex-H₂O-PBS, Ex-OG-PBS, Con-H₂O-PBS, Con-OG-PBS) encapsulated liposomes were given to macrophage intact groups . Ex mice ran to volitional fatigue on a treadmill for 3 consecutive days and OG mice were fed a solution of 50% OG in their drinking water for 10 consecutive days prior to infection. Fifteen minutes following the final bout of Ex or rest mice were intranasally inoculated with 50µl of a standardized dose of HSV-1. Ex increased morbidity (P<0.001) and symptom severity (P<0.05), but not mortality (P=0.09). The increase in morbidity and symptom severity was blocked by OG consumption for 10 consecutive days prior to exercise and infection (morbidity (P<0.001) and symptom severity (P<0.05)). Depletion of macrophages negated the beneficial effects of OG on reducing susceptibility to infection following exercise stress, as evidenced by an increase in morbidity (P<0.01) and symptom severity (P<0.05). Results indicate that lung macrophages are at least partially responsible for mediating the beneficial effects of OG on susceptibility to respiratory infection following exercise stress.