The objectives of this study were to evaluate the effects of supplementing a blend of prebiotics, probiotics, and hyperimmune dried egg protein on the performance, health, and innate immune responses of Holstein calves during the first 21 d of age. Ninety, day-old Holstein bull calves were completely randomized to 1 of 2 treatment groups: prophylactic or control. Prophylactic calves had a proprietary blend of prebiotics, probiotics, and hyperimmune egg protein (Calf- Pro Plus and Calf Life, C and E Agri Products, Baldwin, ND) added directly to the milk replacer at each feeding. Control calves were fed the milk replacer only. Treatment did not influence the performance of Holstein calves. Among calves that voluntarily refused milk replacer, prophylactic calves refused less (P = 0.005) than control calves over the first 4 d of life. Prophylactic treatment reduced the incidence of enteric morbidity (25.0 vs. 51.1% for prophylactic and control calves, respectively; P = 0.011). However, treatment did not influence either total peripheral leukocyte or differential counts. Furthermore, hematocrit and plasma concentrations of haptoglobin, cortisol, glucose, and urea nitrogen were not different between treatments. Last, ex vivo innate immune responses evaluated at 21 d of age were not different between treatments. Calves fed the combination of prebiotics, probiotics, and hyperimmune egg protein rejected less milk replacer during the first 4 d of the experiment and had fewer days with enteric morbidity than did the control calves.