Objective: To investigate the clinical characteristics and differential diagnosis of chronic neutrophil leukemia (CNL). Methods: The clinical data, characteristics of cell morphology, pathological and immunohistochemical features of bone marrow biopsy from 2 cases of CNL were retrospectively analyzed, and the relevant literatures were reviewed. Results: Both CNL patients were middle-aged male with leukocytosis as primary complaint. The peripheral blood examination revealed an elevated leukocyte counts with mostly mature neutrophils and increased neutrophil alkaline phosphatase (NAP) score. The proliferation of nucleated cells in bone marrow was significantly increased with higher proportion of neutral lobular granulocytes. Both patients were negative for BCR-ABL fusion gene and JAK2 V617F gene mutations. The case 1 was diagnosed as CNL with detection of CSF3R T618I mutation, and presented a feature of chronic myelomonocytic leukemia in the peripheral blood two and a half years later. The condition progressed rapidly thereafter. The granulocytic sarcoma was identified in thoracic vertebras 3 months later and the disease had transformed into acute myeloid leukemia in the 4^th month. The patient was not responsive to the standard chemotherapy regimen combined with Dicitabine, and eventually died of a cerebral hemorrhage. Case 2 was initially diagnosed as leukemia-like reaction, but suffered from massive splenomegaly, aggravation of anemia and increased serum monoclonal IgA-λ 2 years later. The repea-ted examination of bone marrow then showed CNL accompanied with multiple myeloma (MM). Case 2 achieved completely remission for both MM and CNL after chemotherapy with Vanke as the main regimen. Conclusion: CNL is an extremely rare type of chronic leukemia, with non-specific clinical manifestations and complicated prognosis. CNL may coexist with other hematologic neoplasms, and there is a high risk of conversion to AML. The molecular diagnosis standard characte-rized by CSF3R gene mutation is conductive to the diagnosis and treatment of CNL.