CHS is a cutaneous, T cell-dependent, inflammatory reaction mediated mainly by antigen-specific effector T cells. Bortezomib is a proteasome inhibitor that has shown impressive efficacy for the treatment of multiple myeloma. In the current study, we have assessed the effect of bortezomib treatment of CHS in mice and found that bortezomib potently inhibited CHS responses. The attenuation of CHS responses was associated with decreased inflammatory cell infiltration in the challenged skin. Specifically, bortezomib-treated mice showed significantly decreased numbers of CD4(+) and CD8(+) T cells in the challenged skin and draining lymph nodes. Cytoplasmic IFN-gamma production by CD4(+) and CD8(+) T cells in the draining lymph nodes was decreased substantially by bortezomib treatment. Notably, bortezomib enhanced T cell apoptosis by inhibiting NF-kappaB activation during CHS responses. Thus, bortezomib treatment is likely to induce T cell death, thereby suppressing CHS responses by reducing IFN-gamma production. These findings suggest that bortezomib treatment could be a promising strategy for treating autoimmune and inflammatory disease.