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To evaluate the performance of contrast-enhanced sonography with a second-generation contrast agent in assessing the severity of chronic diffuse liver disease and differentiating cirrhotic from noncirrhotic liver disease.Contrast-enhanced sonography was performed after intravenous bolus injection of a second-generation contrast agent in 14 healthy control participants and 160 consecutive patients with cirrhotic and noncirrhotic liver disease (n = 78 and 82, respectively) enrolled between March 2004 and April 2014. The intensity of enhancement in a main hepatic vein was used to determine hepatic vein arrival time, time to peak intensity, and peak contrast enhancement.The hepatic vein arrival time was lower in cirrhotic patients compared with both noncirrhotic patients and controls (mean ± SD, 15.0 ± 2.8, 21.5 ± 3.4, and 25.6 ± 4.7 seconds, respectively; P < .05). The hepatic vein arrival time in noncirrhotic patients was also significantly lower than that in controls (P < .05). The time to peak intensity was significantly lower in cirrhotic patients compared with noncirrhotic patients and controls (40.7 ± 13.7, 49.4 ± 12.8, and 51.2 ± 13.7 seconds; P < .05). A receiver operating characteristic curve analysis revealed that the hepatic vein arrival time more accurately excluded a diagnosis of liver cirrhosis than the time to peak intensity (area under the receiver operating characteristic curve, 0.953 versus 0.694). Specifically, a hepatic vein arrival time cutoff value of 17 seconds excluded liver cirrhosis with 91.1% sensitivity and 93.6% specificity.Contrast-enhanced sonography is a valid alternative method for noninvasive staging of liver diseases. The hepatic vein arrival time could be used to exclude liver cirrhosis in a clinical setting.