Many cancers are associated with hypercoagulability, including multiple myeloma. At least four possible reasons for hypercoagulability have been described in myeloma patients: interference of immunoglobulins on fibrin structure, procoagulant autoantibody production, effects of inflammatory cytokines on endothelium, and acquired activated protein C (APC) resistance. Moreover, injury to endothelium, either by tumor cells or by chemotherapy, may predispose to thrombosis by causing upregulation of adhesion molecules, allowing adhesion of blood cellular elements (platelets, lymphocyte, neutrophils, and tumor cells, which secrete thrombogenic as well as angiogenic substances). In most cases, the pathogenesis of a thrombotic complication in myeloma patients remains unexplained. Administration of chemotherapy may play a larger role in the thrombotic process than a specific abnormality does because thrombotic complications become more prominent after the start of treatment. The recently reported evidence of a non-factor V Leiden APC resistance has increased our understanding of the pathophysiology of this hypercoagulable state.