Lactoferrin (LF) is a cationic iron-binding glycoprotein that is abundantly expressed and secreted from glandular epithelial cells and a prominent component of the secondary granules of polymorphonuclear neutrophils. Various in vitro and in vivo experiments demonstrate anti-microbial, -viral, -mycotic and -inflammatory effects of LF, associated with modulations of the immune system. Effects of oral administered LF on selected immune system parameters were studied in calves. Five calves were fed LF beginning on day 3 of life with colostral milk and starting on day 6 of life milk replacer enriched with 0.16% LF was fed. The average daily intake of LF per calf was 1.5-1.6 g/day. Additional five calves served as control group with identical treatment except for the LF supplementation. At the end of the study (day 61 of life), all calves were slaughtered and various tissues were sampled for histological and gene-expression studies. LF given orally was shown to act as an immunomodulatory agent by enhancing the size of Peyer's patches in the ileum and increasing blood serum immunoglobulin G levels. In addition, the number of peripheral blood leucocytes increased and mRNA levels of various interleukins (IL) such as IL-1beta, IL-8, IL-10 and interferon gamma (IFNgamma) in those cells in response to LF treatment were enhanced. In blood, the mRNA expression of the pro-inflammatory marker genes IL-1beta and IFNgamma decreased over 10-week treatment. Additionally, LF feeding decreased villus sizes in the jejunum. Together these findings emphasize the ability of LF to stimulate prominent immune system parameters and that it has the capacity to modulate the immune responses in a positive way.