Atherosclerosis is a major cause of mortality worldwide. The important role inflammation plays in atherosclerosis is evident through the participation of inflammatory cells in the development and progression of the disease. Thrombin is the central protease of the coagulation cascade, involved in the formation of a hemostatic plug to avoid severe bleeding. In addition, thrombin is a key factor in regulating inflammatory processes, signaling through protease activated receptors. We propose that thrombin may be a relevant factor in the atherosclerosis coagulation-inflammation axis. Human histological data show abundant coagulation activity within atherosclerotic lesions with thrombin activity being related to atherosclerotic plaque development and (in)stability. Animal studies establish that the generated thrombin level relates to progression of atherosclerosis, with hypercoagulability producing advanced atherosclerosis in mice with an Apolipoprotein E-deficient (ApoE(-/-)) background. Several studies show that administration of direct oral anticoagulants, like dabigatran and rivaroxaban, attenuate atherosclerosis development in ApoE(-/-) mice. In this review we explore several mechanisms by which thrombin may operate in modifying the chronic process of atherosclerosis. One of the key elements may be the conversion of thrombin, from a physiological regulator of hemostasis towards an inflammation-mediator under pathophysiological conditions, contributing to a switch in the thrombin-activated protein C (APC) regulation. The ongoing inflammatory activity, indicated by the activation of pro-inflammatory cytokines, neutrophils and neutrophil extracellular traps, drive thrombin generation, while diminishing APC formation. The net result is accelerated pro-inflammatory and pro-thrombotic changes in blood and in the vessel wall. We conclude that these atherogenic influences of thrombin may be clinically relevant in the long-term. Further the treatment with long-term anticoagulant therapy deserves further attention as to its potential, vascular side effects.