Objectives: Multiple myeloma (MM) is nearly always preceded by premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), but at present time we are lacking reliable risk factors and predictors for its progression. Bone marrow angiogenesis plays an important role in the pathogenesis and progression of disease and its inhibition has been recognized as a promising approach in the treatment of patients with MM. The biology behind gradual increase in extent of bone marrow angiogenesis is unclear, and differences in angiogenic cytokine expression and bone marrow angiogenic potential among the various stages of the disease are not fully understood. Therefore the main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow specimens of patients with MGUS and MM. Additionally, we wanted to determine their prognostic significance in MM. Patients and Methods: Ninety-five patients were enrolled in this study; 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM, accompanied with all clinical data and adequate bone marrow biopsy specimens. In addition to traditional method of evaluation angiogenesis by counting microvessel density (MVD) a computer assisted image analysis was used to determine the total count of microvessels per square millimetre, area occupied by microvessels per square millimetre, mean diameter of microvessels and the area occupied by microvessels (as a percentage of the total section area, TVA) on samples immunohistochemically stained with anti-CD34. Double immunohistochemical methods CD138+VEGF and CD138+OPN were used to evaluate expression of VEGF and OPN in bone marrow plasma cells. The expression of OPN has also been studied in extracellular matrix (iOPN) and scored semiquantitatively in two categories, positive and negative. Results: A significant positive correlation was determined between analyzed proteins and angiogenic parameters in the MGUS stage of the disease. In the successive stages of the disease a reversal of the correlation from positive to negative was found with a significant negative correlation in advanced stage (clinical stage III according to Durie-Salmon). All analyzed angiogenic parameters, except mean diameter of microvessels, were significantly higher in the patients with diffuse pattern of bone marrow infiltration, bone marrow fibrosis, active MM, higher clinical stage and evident bone lesions. Furthermore we found that MVD (p=0.004) and total count of microvessels per square millimetre (p=0.028) are important prognostic indicators of patient response to the first-line therapy. The overall survival rates were significantly shorter in patients with negative iOPN (p=0.002) and higher angiogenic parameters, MVD (p=0.05), TVA (p= 0.008), total count of microvessels per square millimetre (p=0.009) and area occupied by microvessels per square millimetre (p=0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p=0.03; HR: 0.44, p=0.04). Conclusion: The results of our study have contributed to a better understanding of the role of VEGF and OPN in the process of bone marrow angiogenesis in patients with MGUS and MM. Our findings in MGUS support the key role of these proteins in the induction of angiogenesis. We believe that computerized microvessel determination could be used as a reliable and more accurate method for quantification of tumor angiogenesis in bone marrow samples of patients with lower plasma cell infiltration. This additional spectrum of information regarding quantity and quality of angiogenesis would enable identifying subset of patients in the early stages of the disease with different course of the disease and poor response to therapy.