Sézary Syndrome is a rare leukemic cutaneous T-cell lymphoma with unknown etiology and an aggressive clinical course. It is characterized by erythroderma, generalized lymphadenopathy and neoplastic CD4+ memory T cells called Sézary cells in the skin, lymph nodes and peripheral blood. The early course of the disease is usually misdiagnosed because skin lesions may be atypical for several years because they mimic other more common benign skin diseases, including atopic dermatitis. For this reason we must carry out further investigations on patients with erythroderma and higher levels of IgE to confirm cutaneous T-cell lymphoma. Histological findings, high CD4/CD8 ratio and presence of Sézary cells in peripheral blood are helpful in reaching a correct diagnosis. The diagnostic process is made even more challenging because the histology is often nonspecific at the beginning and the median duration from the initial appearance of skin lesions to a diagnosis is almost six years. This complex phenotype is associated with a poor clinical outcome and a poor prognosis as an estimated survival rate of five years is only 25% after diagnosis. Sézary syndrome is currently incurable. In general, available therapies are effective in controlling the disease, but they have not been shown to prolong life, with the exception of treatment with methotrexate. The treatment of advanced stages of Sézary syndrome is a huge therapeutic challenge as there is no standard or definite curative treatment regimen. We present a case of a patient with confirmed Sézary syndrome three years after the first appearance of itchy, floury scaling and erythematous skin lesions. After extensive diagnostics and setting the stage of the disease, we started treating him with low doses of methotrexate.