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Abstract Introduction: Chronic B-cell lymphoproliferative disorders (B-CLPDs) comprise a heterogeneous group of malignancies involving the clonal expansion of mature B lymphocytes in the bone marrow, peripheral blood, and lymphoid tissues. Diagnosis is commonly established using flow cytometric immunophenotyping. B-CLPDs may be further categorized based on CD5 expression. CD5 expression is characteristic of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). However, occasional cases, such as marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL) may also express CD5. Co-expression of CD23 is commonly used to distinguish CLL from MCL, however, other rare CD5-positive, CD23-negative cases require further diagnostic workup. Aims: The aim of our study was to evaluate the diagnostic pathway of CD5-positive, CD23-negative B-CLPD cases diagnosed over a two-year period at “Yeolyan” Hematology and Oncology Center. Methods: A retrospective cohort study was conducted at the “Yeolyan” Hematology and Oncology Center (Yerevan, Armenia) using data from patients who underwent flow cytometry analysis over a two-year period (2023–2024). Among 216 patients identified with CD5-positive BCLPDs via flow cytometry, 190 were diagnosed as CLL/SLL based on characteristic immunophenotype. The remaining 26 patients (12.0%) lacked CD23 expression. These cases underwent further diagnostic workup, including histopathology, cytogenetics, and clinical correlation. Two patients refused additional diagnostic procedures and were lost to follow-up thereafter. Results: Of the 26 evaluable CD5-positive, CD23-negative B-CLPD cases, 18 were ultimately diagnosed as CLL/SLL based on the absence of cyclin D1 expression and/or t (11;14) assessed by fluorescence in situ hybridization (FISH). Three patients were diagnosed with splenic marginal zone lymphoma (SMZL) with aberrant CD5 expression, diagnosis was confirmed based on the histological and immunohistochemical examination of bone marrow. Two patients were diagnosed with DLBCL, and one patient was diagnosed with FL. Diagnosis was confirmed based on the histological and immunohistochemical examinations of lymph nodes. Our findings demonstrate the diagnostic diversity of CD5-positive, CD23-negative presentations and highlight the limitations of flow cytometry alone in classifying B-CLPDs. Conclusion: CD5-positive, CD23-negative B-CLPDs encompass a spectrum of distinct lymphoid malignancies. A comprehensive diagnostic approach is crucial to ensure accurate classification and appropriate clinical management.