Oral administration of an antigen can result in local and systemic priming or tolerance and the basis of this dichotomy is poorly understood. The intestinal microenvironment, and factors such as nature of the antigen, dose, genetic background, uptake and concentration of the antigen that gain access to the internal milieu via the mucosa influence these active immunologic processes. Chitosan is a biocompatible natural polysaccharide able to promote the transmucosal absorption of peptides and proteins. The aim of our work was to study the effect of the co-administration of type II collagen (CII) and chitosan during the initial contact of the antigen with the immune system. Sixteen hours after feeding we evaluated several molecular events in mucosal and in systemic lymphoid tissues. We determined in Peyer's patches (PP) and spleen cells the number and activation of T cells, the arrival of the antigens, and the cytokine profile. In PP we found a reduction in the cell number without changes in CD3(+) cells. In spleen, instead, we observed an increase in CD3(+) cells as well as the internalization of the CD3 complex. CII:chitosan-fed animals exhibited a reduced secretion of IL-2 with an increase of IL-10 in PP and spleen respectively. In addition, in PP, CII:chitosan-fed rats showed increased levels of mRNA for transforming growth factor-beta, IL-4 and IL-10. Together, our data suggest that the co-administration with chitosan modifies the uptake and/or the distribution of the relevant antigen, and promotes an anti-inflammatory environment early after feeding.