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Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory case of PTCL-NOS with widely involvement of subcutaneous tissue, which showed an excellent response to Semustine personalized chemotherapy based on the detection finding of positive O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. This is the first english report to indicate that single nitrosourea agent such as Semustine may have good efficacy and safety for widespread subcutaneous involvement of PTCL-NOS with positive MGMT promoter methylation.