: The introduction of new agents in multiple myeloma therapy has increased the overall response rate and improved clinical outcomes, but the increased risk of thrombotic complications impairs the quality of life of patient and the optimal thromboprophylaxis remains unknown. Increasing evidence has shown that statins can prevent venous thrombosis. Hence, we investigated the effects of simvastatin on multiple myeloma serum-related haemostatic imbalance in endothelial cells in vitro. The effects of simvastatin on procoagulant and anticoagulant protein expression were assessed on mixed multiple myeloma serum-treated human umbilical vein endothelial cells (HUVECs). The activity of these proteins was measured by thrombin generation and protein C activation assay. Then, the effects of extracellular signal-regulated kinase (ERK) 1/2 on endothelial activation were assessed by western blot and inhibition assay. We found that simvastatin inhibited multiple myeloma serum-induced expression of procoagulant protein tissue factor and phosphatidylserine and generation of thrombin on HUVECs. In contrast, simvastatin increased multiple myeloma serum-inhibited expression of anticoagulant protein endothelial protein C receptor and activation of protein C on HUVECs. Moreover, simvastatin reversed the multiple myeloma serum-induced prothrombotic phenotype, at least in part, via the inhibition of ERK 1/2 activation in endothelial cells. This study supports the beneficial effects of simvastatin on multiple myeloma serum-induced endothelial haemostatic imbalance, which suggests that simvastatin may serve as a new and appropriate antithrombotic approach for multiple myeloma patients.