Background and objective Rivaroxaban – an oral, direct Factor Xa inhibitor – inhibits thrombus formation and growth in animal models. We have investigated the effects of rivaroxaban on thrombolysis because impaired fibrinolysis is a risk factor for venous thrombosis and it occurs more often in patients who had a myocardial infarction. As the propensity of a clot to be degraded depends on its structure, we tested the effects of rivaroxaban on clot structure and degradability by tissue plasminogen activator (t-PA). This was done in the absence and presence of thrombomodulin because the thrombin - thrombomodulin complex is the activator of TAFI (thrombin-activatable fibrinolysis inhibitor), a potent inhibitor of fibrinolysis. Methods Clots were formed in a microchamber in the presence or absence of rivaroxaban at pharmacological concentrations (0.15 and 0.25 μg/ml). Clot structure was analyzed by confocal microscopy, and permeability calculated by measuring flow rates. Degradation was evaluated by the amount of D-dimers in the eluate of clot perfused with t-PA, in the presence or absence of thrombomodulin. Results Microscopy showed that clots formed in the presence of rivaroxaban had thicker fibers and a looser fibrin structure with larger pores than controls, leading to increased permeation rate (Darcy constant 2.16-fold and 2.45-fold higher than controls with rivaroxaban at 0.15 μg/ml and 0.25 μg/ml, respectively). This clot structure modification renders the clots more susceptible to fibrinolytic enzymes. The degradation of clots containing 0.15 μg/ml of rivaroxaban was 3.6-fold higher than that of control clots, after 90 minutes perfusion with t-PA. In addition, when clots are formed in the presence of thrombomodulin, the degradability is decreased in control, while In the presence of rivaroxaban, fibrin degradation remains enhanced. Conclusion Rivaroxaban increased thrombolysis by t-PA. This was due to a decrease in thrombin generation. Two mechanisms are involved: modification of clot structure, which makes it more accessible to thrombolytic enzymes; and decrease in TAFI activation by the thrombomodulin–thrombin complex. This property of rivaroxaban may contribute to its antithrombotic effect.