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BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia among adults in Western countries; however, it is relatively rare in Asia. It is characterized by abnormal proliferation of lymphocytes in the blood, bone marrow, and lymphatic tissue. The measurement of serum beta-2 microglobulin (B2M) is essential for baseline workup of multiple myeloma and follicular lymphoma patients. CD49d, an adhesion molecule mediating cell-to-cell and cell-to-extracellular matrix interactions, represents a novel and the most reliable immunophenotypic marker regarding prognosis and independent of other markers. OBJECTIVES: This study aimed to assess the level of B2M and CD49d in serum CLL patients and correlates them with treatment response. PATIENTS AND METHODS: this is a prospective cohort study conducted on 70 patients with CLL and 40 healthy people as a control group. Patient groups were divided into two groups: The first group included 38 patients before receiving treatment and the second group included 32 patients posttreatment. Diagnosis was based on lymphocyte count of >5 × 109/L and immunophenotyping. The measurement of level B2M and CD49d in serum patients was done using enzyme-linked immunosorbent assay. RESULTS: there were 53 males and 17 females, the mean age was 59.12 ± 14.23, and the most clinical presentation was lymphadenopathy. Regarding the mean of B2M, it was 2.19 ± 0.86, 1.86 ± 0.58, and 1.41 ± 0.44 in the pre, post, and control groups, respectively, with P = 0.0001. Regarding the mean of CD49d, it was 0.22 ± 0.15, 0.30 ± 0.44, and 0.19 ± 0.13 in the pre, post, and control groups, respectively, with P = 0.211. CONCLUSION: this study showed that CD49d has no clinical impact on the treatment outcome, yet B2M has an important prognostic factor in deciding patients in advance stage.