Sézary syndrome (SS) is a cutaneous T-cell lymphoma characterized by aggressiveness, rarity, and poor outcome. When the disease becomes advanced (from stage IIB), mogamulizumab (MOGA) is a treatment option with potential adverse effects, including mogamulizumab-associated rash (MAR). The similarity between the symptoms of MAR and SS progression can lead to a delay in starting the next line of potentially effective treatment. This case illustrates the difficulties in distinguishing MAR from SS progression during MOGA treatment. In February 2024, a patient received an SS diagnosis, showing symptoms like erythroderma and inguinal lymphadenopathy. The flow cytometry confirmed the blood involvement. MOGA treatment began in April 2025, after three unsuccessful lines of systemic treatment. After the first cycle, the patient developed severe scaling, widespread erythroderma, and fever, raising concerns about MAR. MOGA was temporarily discontinued, and systemic corticosteroid therapy was initiated. A skin biopsy showed non-specific findings. One month later, MOGA was reintroduced, but new skin lesions appeared. Repeated histopathological examination pointed toward SS progression rather than a drug-related complication. The subsequent clinical course was complicated by bacteremia and secondary skin infections. Next, bridging therapy with bexarotene was initiated, and the patient was referred for allogeneic hematopoietic stem cell transplantation. This case emphasizes the diagnostic and treatment difficulties associated with overlapping clinical and histopathologic features of SS and MAR. It also underscores the importance of an individual approach, repeated clinicopathologic evaluations, and multidisciplinary collaboration. Thus, it may help improve treatment outcomes and patient prognosis.