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Background and Purpose—Atrial fibrillation is the most important risk factor for cardioembolic stroke. Thrombi form in the left atrial appendage rather than in the right. The causes of this different thrombogenicity are not well-understood. The goal herein was to compare the activation of the anticoagulant protein C and the thrombomodulin and endothelial protein C receptor/activated protein C receptor expression on the endocardium between right and left atria. Methods—We harvested the atria of 6 monkeys (Macaca fascicularis) and quantified their ability to activate protein C ex vivo and we measured the thrombomodulin and endothelial protein C receptor expression by immunofluorescence. Results—We found the ability to activate protein C decreased by half (P 0.028) and there was lower expression of thrombomodulin in the left atrial endocardium than the right (52.5 19.9 and 72.1 18.8 arbitrary intensity units, mean standard deviation; P 0.028). No differences were detected in endothelial protein C receptor expression. Conclusions—Impaired protein C activation on the left atrial endocardium attributable to low thrombomodulin expression may explain its higher thrombogenicity and play a role in cardioembolic stroke.