Liver tumors are defined using quantitative dynamic contrast-enhanced ultrasound compared to histological diagnosis, respectively, long-term follow-ups. Forty-two focal liver lesions in 39 patients were examined by contrast harmonic imaging over a period of 2 min after bolus injection of 10-ml galactose-based contrast agent. Vascular enhancement was quantified by using a dedicated software that allowed us to place representative regions of interest (ROI) in the center of the lesion, in the complete lesion, in regular liver parenchyma and in representative liver vessels (artery, vein and portal vein). Peak enhancement was judged to be either in the arterial, portal venous or in the late phase of liver perfusion. The lesion was described as hypovascular, isovascular and hypervascular compared to liver parenchyma. Contrast uptake was described as centrifugal or centripetal and peripheral or homogenous, respectively. Characterization of the lesions was performed unenhanced and after contrast by four independent specialists unaware of histology. Diagnosis of malignancy was evaluated by using a receiver operating characteristic (ROC) analysis, also overall accuracy, average sensitivity, specificity and negative and positive predictive values were calculated. Interobserver agreement was defined by the Kappa statistics. Histologic examination revealed 29 malignant [hepatocellular carcinoma (HCC), n=11; cholangiocellular carcinoma (CCC), n=1; lymphoma, n=1; metastases, n=16)] and 7 benign [hemangioma, n=1; focal nodular hyperplasia (FNH), n=4, adenoma, n=2)] lesions. Six benign lesions (hemangioma n=1; FNH n=5) were proved by long-term follow-up. ROC analysis regarding the diagnosis of malignancy showed values from 0.43 to 0.62 (mean 0.57) before and from 0.70 to 0.80 (mean 0.75) after contrast agent, respectively. The average values for sensitivity, specificity, accuracy and negative and positive predictive values were 66, 26, 62, 45 and 73% unenhanced and 83, 49, 73, 65 and 82% after contrast, respectively. The interobserver agreement was 0.54 and 0.65 for unenhanced and enhanced examinations, respectively. Quantitative dynamic contrast-enhanced sonography improves the diagnosis of malignancy in liver lesions.