Bortezomib, a proteasome inhibitor that was originally developed as an inhibitor of nuclear factor-κB pathways, is currently used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The mechanisms of action of this antitumor agent have been studied by several investigators. Here, we explore the underlying mechanisms of bortezomib-induced apoptosis in cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATLL) at the level of mitochondrial membrane injury. In all cell lines including (KMS-12-PE [MM], HUT78 [CTCL], ATN1 [ATLL], and MT4 [ATLL]), antiapoptotic factors such as c-Flip and XIAP were downregulated after exposure to bortezomib, probably via inhibition of nuclear factor-κB signaling. In addition, among the members of the BH3-only family, upregulation of Noxa was consistently seen at both the transcriptional and protein levels in a p53-independent manner after exposure to bortezomib. Repression of Noxa by small interfering RNA partially rescued CTCL and ATLL cells from bortezomib-induced apoptosis. Immunoprecipitation assays indicated time-dependent binding of Noxa and Mcl-1 in all cell types, suggesting that functional repression of Mcl-1 led to the loss of mitochondrial outer membrane potential. Similar results were also obtained in primary tumor cells from patients with ATLL. Taken together, we conclude that bortezomib-induced apoptosis in ATLL and CTCL cells at least partly depends on the upregulation of Noxa and functional repression of Mcl-1, as is also the case in MM and malignant melanoma. (Cancer Sci 2009; 100: 341–348)