To validate the contrast agent-enhanced US Liver Imaging Reporting and Data System (CEUS LI-RADS) algorithm for accurate diagnosis of hepatocellular carcinoma (HCC) and categorization of all nodules encountered in patients at risk for HCC. A single-center retrospective review of 196 nodules in 184 patients at risk for HCC (consisting of 139 HCCs, 18 non-HCC malignancies, and 39 benign nodules) was performed in a three-reader blinded read format, with the use of the CEUS LI-RADS algorithm. Pathologic confirmation was available for 143 nodules (122 HCCs, 18 non-HCC malignancies, and three benign nodules). Nodule sizes ranged between 1.0 and 16.2 cm. Nodules assessed with contrast-enhanced US were assigned various CEUS LI-RADS categories by three blinded readers. CEUS LI-RADS categorization was then compared against histopathologic findings, concurrent CT, and/or MR images or follow-up imaging to assess diagnostic accuracy of CEUS LI-RADS. In addition, the proportion of HCC in all LI-RADS (LR) categories, univariable and multivariable feature analysis, and interrater agreement using Light κ were determined. The LR-5 category, determined through radiologist categorization of nodules using the CEUS LI-RADS criteria, showed sensitivity, specificity, positive predictive value, and negative predictive value of 86% (119 of 139), 96% (55 of 57), 98% (119 of 121), and 73% (55 of 75), respectively, for the diagnosis of HCC. Two false-positive cases of LR-5 included a cholangiocarcinoma and a combined hepatocellular and cholangiocarcinoma. The remainder of the cholangiocarcinomas in the sample (n = 8) were appropriately categorized as LR-M. Multivariable logistic regression analysis showed that washout of greater than 60 seconds was the contrast-enhanced US feature most predictive of HCC diagnosis, whereas washout of less than 60 seconds was the feature most predictive of nonhepatocellular malignancy. The proportion of HCC nodules categorized in the LR-M and LR-4 categories was 35% and 20%, respectively. Light κ agreement between readers for LI-RADS categorization was 90%. This study showed excellent specificity for the CEUS LI-RADS LR-5 category, allowing for confident imaging diagnosis of HCC, without necessity for pathologic confirmation. In addition, there was accurate differentiation of HCC from non-HCC malignancies and benign nodules. Only a single cholangiocarcinoma was misdiagnosed as category LR-5, with the remainder of the cholangiocarcinomas in the sample appropriately characterized as category LR-M.Keywords: Abdomen/GI, Evidence Based Medicine, Liver, Neoplasms-Primary, Ultrasound-Contrast© RSNA, 2020.