Deep vein thrombosis (DVT) is a major origin of morbidity and mortality. While DVT has long been considered as blood coagulation disorder, several recent lines of evidence demonstrate that immune cells and inflammatory processes are involved in DVT initiation. Here, we discuss these mechanisms, in particular, the role of immune cells in endothelial activation, and the immune cascades leading to expression of adhesion receptors on endothelial cells. We analyze the specific recruitment and functional roles of different immune cells, such as mast cells and leukocytes, in DVT. Importantly, we also speculate how immune modulation could be used for DVT prevention with a lower risk of bleeding complications than conventional therapeutic approaches.