Abstract The purpose of this study was to evaluate the effect of a feed additive (OmniGen-AF®, reported to have immune modulating activity) on innate immunity and health events during the periparturient period in dairy heifers when immunity is suppressed. From 60 days prepartum through calving, supplemented heifers (n=20) received OmniGen-AF® daily and were compared with unsupplemented controls (n=20). Blood leukocyte innate immune activity (phenotype markers, phagocytic activity, and reactive oxygen species—ROS production) was measured prior to feeding (60 days prepartum), 30 days later, and on days 1, 7, 14, and 30 postpartum. Adverse health events (udder edema, ketosis, displaced abomasum, and death) and milk production were measured at calving and into early lactation. The fraction of leukocytes with measurable CD62L (l-selectin) on their surface from supplemented heifers tended to be greater during the periparturient period in treated heifers than controls (p=0.100). Likewise, leukocyte phagocytosis of Escherichia coli and Staphylococcus aureus during this time period tended to be greater in heifers supplemented with OmniGen-AF® (p=0.100). Conversely, ROS production in response to phorbol myristate acetate or when leukocytes were stimulated with killed S. aureus lysate tended to be greater among control heifers compared with supplemented animals (p=0.100). Supplemented heifers exhibited fewer incidents of udder edema than controls (p=0.030) and tended to exhibit a lower rate of new cases of mastitis (p=0.098); however, no differences were observed in milk somatic cell counts or level of milk production. Results demonstrate a positive role of OmniGen-AF® in amplifying leukocyte function consistent with antibacterial activity during the periparturient period, and support the continued study of dietary supplementation to enhance mammary gland health in dairy cows.