INTRODUCTION: The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) treated with thalidomide- and lenalidomide-based regimens is high. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population. PURPOSE: To determine the absolute rates of VTE with and without different thromboprophylactic agents in patients with newly diagnosed or previously treated MM receiving thalidomide- or lenalidomide-based regimens. RESULTS: Patients with newly diagnosed MM treated with thalidomide in combination with dexamethasone have a VTE risk of 4.1 (95% CI, 2.8-5.9) per 100 patient-cycles. Therapeutic doses of anticoagulants seem to provide the largest absolute risk reduction of VTE. The rate of VTE in patients with previously treated MM receiving thalidomide in combination with dexamethasone is 0.8 (95% CI, 0.1-2.1) per 100 patient-months. A combination of lenalidomide and dexamethasone is associated with of risk of VTE of 0.8 (95% CI, 0.07-2.0) per 100 patient-cycles and 0.7 (95% CI, 0.4-0.9) per 100 patient-cycles in patients with newly diagnosed and previously treated MM, respectively. Similarly, the rates of VTE in patients also receiving thromboprophylaxis with aspirin were 0.9 (95% CI, 0.5-1.5) and 0.6 (95% CI, 0.01-2.1), respectively. CONCLUSION: Patients with newly diagnosed or previously treated MM receiving thalidomide- or lenalidomide-based regimens in combination with dexamethasone are at high risk of VTE. The benefit of various types of thromboprophylaxis is difficult to quantify in patients with MM receiving immunomodulatory therapy, especially in those receiving lenalidomide-based therapy or who have previously treated MM. Randomized controlled trials are needed to address this important clinical need.