Measurement of hepatic venous pressure gradient (HVPG) is currently widely adopted to provide an estimate of portal pressure gradient (PPG) in the diagnosis and treatment of portal hypertension associated with liver cirrhosis. Despite the well-documented clinical utility of HVPG, it remains poorly understood how the relationship between HVPG and PPG is affected by factors involved in the pathogenesis and progression of cirrhosis. In the study, a computational model of the hepatic circulation calibrated to in vivo data was developed to simulate the procedure of HVPG measurement and quantitatively investigate the error of HVPG relative to PPG under various pathophysiological conditions. Obtained results confirmed the clinical consensus that HVPG is applicable to the assessment of portal hypertension caused by increased vascular resistance located primarily at the sinusoidal and postsinusoidal sites rather than at the presinusoidal site. On the other hand, our study demonstrated that the accuracy of HVPG measurement was influenced by many factors related to hepatic hemodynamics even in the case of sinusoidal portal hypertension. For instance, varying presinusoidal portal vascular resistance significantly altered the difference between HVPG and PPG, while an enhancement in portosystemic collateral flow tended to improve the accuracy of HVPG measurement. Moreover, it was found that presinusoidal and postsinusoidal vascular resistances interfered with each other with respect to their influence on HVPG measurement. These findings suggest that one should take into account patient-specific pathological conditions in order to achieve a better understanding and utilization of HVPG in the clinical practice.