Background Multiple myeloma (MM) is a blood tumor associated with the proliferation of abnormal plasma cells in the bone marrow (BM). CD45 is a common leukocyte antigen. It is present on all immunological and hematological cells except mature erythrocytes and platelets. Subjects and method This prospective cohort study included 96 MM patients subjected to thorough history taking and full examination, including body mass index (BMI) calculation. The laboratory investigations included complete blood count (CBC), serum creatinine, serum albumin, serum β2-microglobin, lactate dehydrogenase (LDH), and calcium. Bone marrow (BM) aspiration and biopsy, protein electrophoresis, and immune fixation were performed. Conventional chromosome analysis and fluorescent in situ hybridization (FISH) were performed for t (4;14), t (14;16), t (14,20), 17p deletion, or chromosome 1q amplification. Immunological characterization was performed on BM cells using the panel of CD45, CD19, CD20, CD38, CD138, CD56, and kappa and lambda Ags. Radiological studies included skeletal survey, low-dose computerized tomography (CT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT scan. Results Hemoglobin levels, platelet count, and serum albumin were significantly higher in CD45-positive patients compared to CD45-negative patients (P<0.001, 0.04, and <0.0001, respectively). Serum creatinine, β2-microglobulin, and calcium were significantly lower in the CD45-positive group compared to the CD45-negative group (P=0.006, <0.001, and < 0.001, respectively). Bence Jones proteinuria was significantly more frequent in CD45-negative patients (P=0.001), while LDH showed no significant difference between the two groups (P=0.185) Conclusion CD45 negativity is related to poor prognosis in MM. Higher serum LDH levels and high-risk cytogenesis were adverse prognostic factors, as well.