Aging is associated with increasing inflammation and oxidative stress in the body, both of which can have negative health effects. Successful attenuation of such processes with dietary countermeasures has major public health implications. Soy foods, as a source of high-quality protein and isoflavones, may improve such indices, although the effects in healthy postmenopausal women are not well delineated. A single-blind, randomized controlled trial was conducted in 31 postmenopausal women who were assigned to consume 3 servings of soy (n = 16) or dairy (n = 15) milk per day for 4 weeks. Parameters of systemic inflammation (tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6)) and the oxidative defense system (superoxide dismutase (SOD), glutathione peroxidase, cyclooxygenase-2) were measured post supplementation, before and after an eccentric exercise bout performed to elicit an inflammatory response. A significant group-by-time effect for plasma TNF-alpha was observed (p = 0.02), with values in the dairy group increased post supplementation and then decreasing into the postexercise period. Additionally, significant time effects were observed for plasma SOD (p < 0.0001) and IL-6 (p < 0.0001) in the postexercise period. Overall results from our study do not support the notion that 4 weeks of daily soy milk ingestion can attenuate systemic elevations in markers of inflammation or oxidative defense. However, data do suggest that the downhill-running protocol utilized in this study can be effective in altering systemic markers of inflammation and oxidative defense enzyme activity, and that the ingestion of soy may help prevent fluctuations in plasma TNF-alpha.