Previous studies have demonstrated the importance of the ubiquitin-proteasome pathway in the immune response to bacterial pathogens. To investigate the role of this system in the context of leprosy, Mycobacterium leprae-stimulated peripheral blood mononuclear cells (PBMC) were treated with the proteasome inhibitor MG132 to assess the levels of apoptosis and cytokine secretion. The results showed that the inhibition of proteasome activity significantly reduced M. leprae-mediated cell death. In addition, MG132 treatment led to a significant decrease in M. leprae-induced TNF-alpha and IL-10 secretion. Together, these results suggest that modulations of the ubiquitin-proteasome pathway may participate in the human response to M. leprae.