The recommendations for antithrombotic treatment after left atrial appendage closure (LAAC) remain empirical, and no data exist on the changes in hemostatic markers associated with LACC. The objective of the present study is to determine the presence, degree, and timing of changes in the markers of platelet and coagulation activation after LAAC. Forty-three patients (mean age 76 ± 9 years, 23 men) with atrial fibrillation who underwent successful LACC with the Watchman (n = 27) or Amplatzer Cardiac Plug (n = 16) devices were included in the study. Patients received antiplatelet therapy after LAAC (aspirin + clopidogrel: 27 patients; single antiplatelet therapy with aspirin or clopidogrel: 16 patients). Prothrombin fragment 1+2 and thrombin-antithrombin III were used as markers of coagulation activation, and soluble P-selectin and soluble CD40 ligand were used as markers of platelet activation. Measurements of all hemostatic markers were performed at baseline just before the procedure, followed by days 7, 30, and 180 after LAAC. Prothrombin fragment 1+2 and thrombin-antithrombin levels increased from 0.27 nmol/L and 4.68 ng/ml, respectively, at baseline to peak values of 0.43 nmol/L and 9.76 ng/ml, respectively, at 7 days, partially returning to baseline levels at days 30 and 180 after LAAC (p <0.001 for both markers). No clinical or procedural factors were associated with a greater increase in the markers of coagulation activation after LAAC. Levels of soluble P-selectin and soluble CD40 ligand did not change at any time after LAAC. In conclusion, transcatheter LAAC is associated with significant activation of the coagulation system, yet without evidence of significant platelet activation.