During the process of class II MHC assembly and cell surface expression, the class II-associated invariant chain peptide (CLIP) is removed from the peptide-binding groove of MHC, a task mediated by H-2M. This allows binding and presentation of peptide epitopes. We have previously shown that exogenously added CLIP interferes with this process and down-regulates the cell surface expression of class II molecules. In this study, we explored the effect of exogenously added CLIP on antigen-specific immune responses. In vivo studies with CLIP and various peptide and protein antigens with different affinities for I-A(d) molecules demonstrated that CLIP variably affects the T cell-mediated immune responses. Immunization with CLIP along with the antigen induced a shift from a T(h)1- to T(h)2-like response as determined by the cytokine profile and antibody isotype. These results suggest that the presence of exogenous CLIP can significantly influence the presentation of antigen by class II MHC molecules to CD4 T cells and thereby modulate immune responses. Exogenously added CLIP rapidly localized into the subcellular compartment of antigen-presenting cells where MHC class II molecules are present. We suggest that exogenous CLIP reduces the loading of peptides on the class II molecules, thus down-regulating MHC-peptide complexes on the cell surface. Alternatively, CLIP may bind to cell surface class II molecules and this complex is rapidly internalized resulting in reduced cell surface MHC class II expression. The reduced level of MHC-peptide complexes favors the activation of T(h)2 cells over T(h)1 cells. These results have implications in the regulation of immune responses, particularly the prevention of certain autoimmune diseases where T(h)1-type responses are pathogenic and T(h)2-type responses are protective.