Mycosis fungoides (MF) and Sézary syndrome (SS) are representative cutaneous lymphomas. In their early stage, a small number of tumor cells and a large number of non-malignant cells form a Th1-dominant tumor microenvironment. Increase in malignant T cells is accompanied by a decrease in CD8-positive T cells, with a shift toward a Th2-dominant milieu in advanced-stage lesions. The etiologies of MF/SS are diverse, and the underlying pathogenetic mechanisms are yet to be elucidated. Advanced MF/SS is known to be highly sensitive to Staphylococcus aureus, and the majority of deaths are caused by severe infections. The susceptibility to infection is associated with barrier dysfunction and immunosuppression, which are the main symptoms of MF. In recent years, skin-colonizing S. aureus has been identified to not only cause severe infections but also play an important role in the pathogenesis of MF/SS. Staphylococcal superantigens activate the proliferation of tumor cells and induce CD25 upregulation, FOXP3 expression, IL-17 expression, and miR-155 expression. Alpha-toxin eliminates non-neoplastic CD4-positive cells and CD8-positive cells and plays a major role in tumor cell selection. Lipoprotein may also be associated with the induction of Th2-dominant milieu. Antibiotic therapy for S. aureus eradication has been reported to cause considerable clinical improvement in the majority of individuals with advanced cutaneous T-cell lymphoma. Therefore, S. aureus may be a novel target for the treatment of advanced-stage MF/SS in the future.