INTRODUCTION Little is known about the CD40L-CD40 pathway in hematologic malignancies, especially in multiple myeloma (MM). OBJECTIVES The aim of the current study was to evaluate serum soluble CD40 ligand (sCD40L) concentrations in patients with newly diagnosed MM prior to treatment at different stages of disease, compared with healthy controls. To assess the clinical significance of sCD40L, we assessed correlations between the levels of sCD40L and those of angiogenic cytokines: interleukin 6 (IL-6), soluble receptor of IL-6 (sIL-6R), tumor necrosis factor α (TNF-α), soluble vascular cell adhesion molecule 1 (sVCAM-1), and platelet-derived growth factor AB (PDGF-AB), as well as with well-established biomarkers of MM activity (lactate dehydrogenase activity and percentage of bone marrow plasma cells) and with a marker of platelet activation (β-thromboglobulin). PATIENTS AND METHODS The study group consisted of 41 patients with newly diagnosed MM; the control group consisted of 30 healthy subjects. The level of sCD40L was determined using an enzyme-linked immunosorbent assay. RESULTS The level of sCD40L was significantly higher in patients with MM than in controls and increased with the stage of the disease. Moreover, it significantly correlated with the levels of IL-6, sIL-6R, sVCAM-1, PDGF-AB, as well as the levels of MM activity markers and β-thromboglobulin. CONCLUSIONS Our findings indicate that increased serum sCD40L levels may be related to angiogenesis in patients with MM. This protein has potential clinical usefulness in MM and may be considered as an additional prognostic marker. The correlation of sCD40L with β-thromboglobulin may indicate that in patients with MM sCD40L derives from activated platelets.