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As for other malignancies, multiple myeloma is associated with an increased risk of venous thromboembolism (VTE). The incidence of VTE is estimated as 8 to 22 per 1,000 person-years; risk factors can be patient related (advanced age, other risk factors shared with the general population), disease related, and treatment related. Disease-related risk factors can derive from the monoclonal component (rarely hyperviscosity or inhibition of natural anticoagulants) or hypercoagulability sustained by inflammatory cytokines (increased von Willebrand factor, factor VIII, fibrinogen levels, decreased protein S levels, acquired activated protein C resistance). The 1 to 2% baseline of incident VTE associated with conventional therapies as melphalan and prednisone is at least doubled by the use of doxorubicin or other chemotherapeutic agents. The VTE rate associated with thalidomide or lenalidomide as monotherapy is similar, whereas combination with high-dose dexamethasone or multiple chemotherapeutic agents induces a multiplicative effect on the VTE rate up to 25%. Low-molecular-weight heparin (LMWH), fixed low-dose warfarin, and aspirin are acceptable strategies for antithrombotic prophylaxis, reducing VTE to 5 to 8% in thalidomide-treated patients and 1 to 3% in lenalidomide-treated patients. LMWH shows an advantage in efficacy not statistically significant. Prophylaxis should be tailored considering individual risk factors for VTE, the stage of disease, the possible occurrence of thrombocytopenia, or renal insufficiency.