Angiogenesis is an important hallmark in multiple myeloma (MM) pathogenesis, with the participation of various versatile molecules. Interleukin-20 (IL-20) is a pro-inflammatory cytokine with diverse angiogenic properties. Our purpose was to estimate the possible impact of IL-20 on MM angiogenesis and disease activity. We measured serum levels of IL-20 along with levels of vascular endothelial growth factor (VEGF), basic-fibroblast growth factor and angiopoietin 2 in 58 active MM myeloma patients, in 32 of them who responded to bortezomib-based therapy and in 20 controls. We also measured bone marrow microvasclular density (MVD) by immunohistochemical method. Serum levels of all cytokines and bone marrow MVD were higher in active MM patients compared to controls and responders to bortezomib-based therapy (p < 0.001 in all cases). They were also in parallel with International Staging System stages (p < 0.001 for all cases). Serum levels of IL-20 correlated positively with levels of angiogenic cytokines and bone marrow MVD (p < 0.01 for MVD, p < 0.002 for VEGF and p < 0.001 for the other cases). Our results strongly suggest that serum IL-20 concentrations participate actively in the pathophysiology of MM progression. Therefore, it could be used as an indicator of the disease progression and angiogenesis processes.