Background: Hypertension is a widespread disease involving frequent thrombotic complications. Blood pressure variability (BPV) has recently been shown to be associated with end-organ damage and cardiovascular events. However, the pathogenesis of the relation between BPV and cardiovascular events has not yet been explained. Soluble endothelial protein C (sEPCR) exhibits a procoagulant effect by reducing the anticoagulant and anti-inflammatory effects of protein C and activated protein C. The purpose of this study was to evaluate sEPCR levels in hypertensive individuals and the parameters affecting that level, particularly BPV. Methods: Fifty-one newly diagnosed hypertensive subjects and 31 healthy individuals were included in the study. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed after office control, and simultaneous 24-h urine was collected. BPV was calculated with average real variability (ARV) from ABPM data. Blood specimens were collected under appropriate conditions for sEPCR levels and biochemical tests. sEPCR levels were compared between the patient and healthy groups, after which parameters affecting sEPCR elevation in the hypertensive group were evaluated. Results: sEPCR levels were significantly high in the hypertensive group (p < 0.05). At multivariate regression analysis in the hypertensive group, sEPCR was determined to be independently associated with 24-h systolic ARV (beta = 0.572, p < 0.05) and 24-h urine Na (beta = 0.428, p < 0.05). Conclusion: In our study, sEPCR was high in hypertensive individuals, and this elevation was related to ARV and urine Na excretion independently of mean blood pressure.