The HepQuant SHUNT test quantifies hepatic functional impairment from the simultaneous clearance of cholate from the systemic and portal circulations for the purpose of monitoring treatment effects or for predicting risk for clinical outcome. Compartmental models are defined by distribution volumes and transfer rates between volumes to estimate parameters not defined by noncompartmental analyses. Previously, a noncompartmental analysis method, called the minimal model (MM), demonstrated reproducible and reliable measures of liver function (Translational Research 2021). The aim of this study was to compare the reproducibility and reliability of a new physiologically based compartmental model (CM) vs the MM. Data were analyzed from 16 control, 16 nonalcoholic steatohepatitis (NASH), and 16 hepatitis C virus (HCV) subjects, each with 3 replicate tests conducted on 3 separate days. The CM describes transfer of cholates between systemic, portal, and liver compartments with assumptions from measured or literature-derived values and unknown parameters estimated by nonlinear least-squares regression. The CM was compared to the MM for 6 key indices of hepatic disease in terms of intraclass correlation coefficient (ICC) with a lower acceptable limit of 0.7. The CM correlated well with the MM for disease severity index (DSI) with R2 (95% confidence interval) of 0.96 (0.94-0.98, P < 0.001). Acceptable reproducibility (ICC > 0.7) was observed for 6/6 and 5/6 hepatic disease indices for CM and MM, respectively. SHUNT, a measure of the absolute bioavailability, had ICC of 0.73 (0.60-0.83, P = 0.3095) for MM and 0.84 (0.76-0.90, P = 0.0012) for CM. The CM, but not the MM, allowed determination of anatomic shunt and hepatic extraction and improved the within individual reproducibility.