The pathological consequences of decreased protein Z (PZ) and/or Z-dependent protease inhibitor (ZPI) levels remain as yet unclear, despite a growing body of evidence which supports their involvement in an increased thrombotic risk. The purpose of the present study was 2-fold: to evaluate plasma concentrations of protein Z and ZPI in patients with essential thrombocythemia (ET) and to determine their significance in thrombotic complications. The median (range) plasma concentrations of PZ in our patients with ET were lower, but not significantly, than in healthy individuals: PZ (1.42 mu g/mL, 0.36-3.14 mu g/mL vs 1.6 mu g/mL, 0.75-2.56 mu g/mL, P = .08). On the other hand, the median (range) plasma concentrations of ZPI in the said patients with ET were meaningfully lower than in the reference group: ZPI (3.22 mu g/mL, 0.85-6.97 mu g/mL vs 4.41 mu g/mL, 1.63-7.83 mu g/mL, P = .0004). More importantly, the study revealed a statistically significant lower concentration of PZ and ZPI in patients with the presence of the JAK2V617F mutation relative to patients without the mutation, for PZ: 1.38 mu g/mL, 0.36-2.6 mu g/mL versus 1.63 mu g/mL, 0.88-3.14 mu g/mL, P = .03, and ZPI 2.89 mu g/mL, 0.85-5.91 mu g/mL versus 3.61 mu g/mL, 1.53-6.97 mu g/mL, P = .002. Additionally, significant differences between the concentrations of PZ and ZPI were found in patients with venous thrombotic episodes compared to healthy individuals, for PZ: 1.23 mu g/mL, 0.82-1.99 mu g/mL versus 1.6 mu g/mL, 0.75-2.56 mu g/mL, P = .043, and ZPI: 2.42 mu g/mL, 0.85-4.21 mu g/mL versus 4.41 mu g/mL, 1.63-7.83 mu g/mL, P < .0001. To recapitulate, our results suggest that the deficiency of PZ may increase tendency to thrombosis in patients with ET.