Purpose: To compare subharmonic aided pressure estimation (SHAPE) with pressure catheter-based measurements in human patients with chronic liver disease undergoing transjugular liver biopsy. Materials and Methods: This HIPAA-compliant study had U.S. Food and Drug Administration and institutional review board approval, and written informed consent was obtained from all participants. Forty-five patients completed this study between December 2010 and December 2011. A clinical ultrasonography (US) scanner was modified to obtain SHAPE data. After transjugular liver biopsy with pressure measurements as part of the standard of care, 45 patients received an infusion of a microbubble US contrast agent and saline. During infusion, SHAPE data were collected from a portal and hepatic vein and were compared with invasive measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. Results:- The 45 study patients included 27 men and 18 women (age range, 19-71 years; average age, 55.8 years). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the hepatic venous pressure gradient (HVPG) (R = 0.82). Patients at increased risk for variceal hemorrhage (HVPG ≥ 12 mm Hg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (1.93 dB ± 0.61 [standard deviation] vs 21.47 dB ± 0.29, P < .001), with a sensitivity of 100% and a specificity of 81%, indicating that SHAPE may be a useful tool for the diagnosis of clinically important portal hypertension. Conclusion: Preliminary results show SHAPE to be an accurate noninvasive technique for estimating portal hypertension.