Abstract Skin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to elucidate the mechanisms of mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor β chain repertoire in ATL patients’ peripheral blood mononuclear cells (PBMCs) before and after mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without mogamulizumab. Immune-related gene expression in PBMCs before and after mogamulizumab was also assessed (n = 24). Mogamulizumab treatment resulted in CCR4+ T-cell depletion, and the consequent lymphopenia provoked homeostatic CD8+ T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD8+ T cells that proliferated and diversified after mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR4+ T-cell depletion and increased CD8+ T-cell proliferation and diversification. Thus, lymphocyte-depleting mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of mogamulizumab-induced skin-related AEs.