Case report: A 31-year-old woman presented at a primary care physician with a dry cough and a sore throat that had persisted for one month. A cold was diagnosed, but dyspnea gradually developed. A chest X-ray and computed tomography (CT) revealed a bulky mediastinal mass and several enlarged lymph nodes. Positron emission tomography/computed tomography (PET-CT) imaging showed increased 18-fluoro-deoxyglucose uptake in the bilateral supraclavicular, axillary, mediastinal, hilar, and paraaortic lymph nodes (maximum standardized uptake value [SUVmax], 13.4). A lymph node biopsy showed destruction of the basic structure, hyperplastic fibrous connective fibrous tissue and cohesive clusters and sheets of large malignant cells with a clear, vacuolated cytoplasm and sharply-defined borders. Flow cytometry could not determine the phenotype of the tumor cells. Immunostaining at our hospital showed that the tumor cells expressed CD15, CD30, and CD79a but not CD2, CD3, CD10, or CD20. We initially diagnosed clinical stage 3, CD20-negative diffuse large B-cell lymphoma (DLBCL) and started the patient on the original intensive treatment protocol for advanced, aggressive lymphoma (ML5 protocol). The patient partially responded to the first CHOP-like regimen (doxorubicin 40mg/m2 day1,5,9, vindesine 3mg/body day1,5,9, cyclophosphamide 1000mg/m2 day2,6,10, prednisolone 60mg/m2 day1-10) and then an etoposide-based second regimen(etoposide 100mg/m2 day1-3, 8-10, mitoxantrone 8mg/m2 day1, 8, cyclephosphamide 400mg/m2 day2, 9, prednisolone 60mg/m2 day1-3, 8-10, procarbazine 100mg/m2 day1-10) resulted in a complete response (CR) on PET-CT images. The Department of Pathology, Okayama University, Japan found that the tumor cells were CD79a-, Bob.1-, Oct.2-, indicating a syncytial variant of nodular sclerosis classical Hodgkin lymphoma (NSCHL). Discussion: A syncytial variant of NSCHL has been described in Cancer (1990), and this disease is statistically more advanced at diagnosis and often accompanied by huge mediastinal masses that require treatment after diagnosis. We applied the intensive chemotherapy used for DLBCL to our patient, but seven of eight other patients achieved CR after the administration of MOPP (mechlorethamine, vincristine, procarbazine, prednisolone) or ABV (doxorubicin, bleomycin, vinblastine) regimens. Therefore, awareness of this variant is needed at initial diagnosis to ensure appropriate treatment.