The objective of this pilot study was to investigate the acute effects on circulating lymphocyte subsets, antioxidant status, and cytokine profile after consumption of EpiCor(®) (EP) (Embria Health Sciences, Ankeny, IA, USA), a dried fermentate produced from Saccharomyces cerevisiae, using a placebo-controlled randomized crossover study design with 12 healthy adult human subjects. EP contains high levels of bioavailable antioxidants and strongly activates natural killer (NK) cells in vitro. EP consumption has been shown to increase erythrocyte hematocrit levels, boost mucosal immune protection, reduce cold/flu symptoms, reduce seasonal allergy symptoms and the need for rescue medication, and increase salivary secretory immunoglobulin A levels. This warranted further study on immune effects in humans. A within-subject analysis of data collected before and at 1 and 2 hours after consumption of a single dose of 500 mg of EP versus placebo was performed. A transient reduction in circulating T and NK cell numbers was observed 2 hours post-consumption, suggesting that homing and recirculation of these cells, as part of healthy immune surveillance, were supported by EP. The increased expression of activation markers on the CD3(-) CD56(+) NK cell population was significant for CD69 at 1 hour post-consumption (CD25, P<.07; CD69, P<.05), whereas for CD25 it was significant at 2 hours after consumption (CD25, P<.03; CD69, P<.15). A rapid increase in serum interferon-γ was observed at 1 hour post-consumption (P<.07; after removal of two outlying data sets, P<.05) and may have contributed to the effects seen on NK and T cell subsets. Significant increase in serum antioxidant protection was seen 2 hours after consumption (P<.04). Thus consumption of a single 500 mg dose of EP provides a rapid and transient effect on the trafficking and activation status of specific lymphocyte subsets, as well as increased antioxidant protection.