Abstract: Objective: To explore the clinicopathologic characterisitcs, diagnosis and differential diagnosis of CD4 +/ CD56+ hematodermatic neoplasm (CD4 +/CD56+ HN).Methods:Data of the5 patients who were diagnosed as CD 4 +/ CD56+ HN, based on the related criteria of 2005 WHO-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas, was investigated. Bone marrow biopsy was conducted in all 5 pa-tients, skin biopsy was conducted in 3 patients, and superficial lymph node biopsies were conducted in 4 patients. Histologi -cal specimens were fixed using routine formalin neutral buffered solution and subsequently embedded in paraffin. Sections were stained with hematoxylin and eosin. Immunohistochemistry was conducted using Elivision methods. Results: There were4 males and 1 female, with a median age of 47years (range, 8～73). Three of the 5 patients presented with asymp -tomatic multiple skin lesions that were salmon pink to mauve macules, papules, plaques or subcutaneous nodules. The oth -er two patients presented with superficial lymphadenectasis without skin lesions. Histologically, tumour cells infiltrated the dermis in 3 cases, sparing the epidermis. Blood vessel destruction and necrosis were absent. The architecture of lymph nodes was partially destroyed in 4 cases. Tumor cells involved the interfollicular zone and medulla, similar to a pattern of leukemic infiltration. The degree of bone marrow involvement was moderate to severe ( 4 cases) with a pattern of focal or diffuse infiltration by the tumor cells. Microscopically the tumor cells were medium-sized and displayed a round or slightly ir-regular-shaped nucleus with dispersed chromatin. The morphology of the tumor cells was similar to lymphoblasts or mono -blasts. The results of immunohistochemistry showed the following results: in the immunophenotypical characterization of the tumors, there was expression of CD 4 (80%,4/5), CD 56(100 %,5/5), CD 43(100 %,4/4), CD 45(100 %,3/3) and CD123 (100 % ,2/2), whereas CD 117 , MPO, Lysozyme, CD 68, PAX 5, CD20and CD3 were not expressed. Two of the patients were treated with combined chemotherapy and died of progression of disease at 26and 11months after diagnosis.Conclusions: CD4 +/CD56+ HN is a highly aggressive, non-myeloid and non-lymphoid hematopoietic neoplasm with distinct clinico-pathologic features. Tissue involvement generally includes skin, bone marrow and lymph node. The neoplastic cells are devoid of lymphoid and myeloid lineage specific markers and should be discriminated from various types of myeloid and lymphoid neoplasms such as cutaneous lymphoma, myeloid sarcoma and acute leukemia.