Objective was to evaluate the effect of RPC supplementation (0 or 60 g/d of ReaShure, Balchem Corp., New Hampton, NY) and excess or maintenance intake of energy on indicators of immune function of early lactating multiparous Holstein cows. Cows (n = 93) were fed prepartum high energy (HE; 1.63 Mcal NEL/kg DM; 58% corn silage) or controlled energy (CE; 1.40 Mcal NEL/kg DM; 37.5% wheat straw) diets in ad libitum amounts with or without RPC. The RPC was top-dressed on TMR daily from −21 d to 21 d postpartum (PP). Whole blood was stimulated with LPS in vitro at 3 and 14 d PP. Relative transcript abundance (RTA) of inducible nitrous oxide synthase (iNOS) and select cytokines from WBC was measured by RT PCR using 3 housekeeping genes after 6 h of exposure with or without LPS. The neo-antigen hen-egg lysozyme (HEL) was injected s.c. at −4, −2, and 0 wk PP. HEL-specific IgG in plasma was measured at −4, −2, 0, 1, 2, 3, 4, and 7 wk PP. Acute phase proteins were measured in plasma at 0, 1, 2, 3, and 5 wk PP. Data were analyzed by ANOVA for repeated measures using the MIXED procedure of SAS. Significance was declared at P < 0.05. The RTA of cytokines and iNOS were increased by LPS at both days PP. The RTA of the proinflammatory cytokine, IL-6 (-LPS), tended to be less in WBC of RPC-fed cows (1.56 vs. 0.88). In contrast, the RTA of IL-8, IL-1B, and iNOS from -LPS cells were at least 50% greater at both days PP for cows fed RPC. The RTA of IL-8 and IL-10 after LPS stimulation of WBC from RPC-fed cows decreased from 3 to 14 d PP whereas that of cows not fed RPC remained constant (RPC by day PP interaction). Feeding HE prepartum resulted in greater RTA of IL-8 and TNFa across days PP. Mean plasma concentration of haptoglobin was unchanged but fibrinogen was lower at wk 1 PP of cows fed RPC. Responses of plasma IgG to lysozyme injections were not affected by treatments. Collectively, feeding CE diets prepartum or supplementing RPC to periparturient cows produced changes in WBC cytokine production during the first 3 wk of lactation that are potentially important for regulating innate and adaptive immune responses.