BACKGROUND & AIMS: The European Association for the Study of the Liver (EASL) criteria and, more recently, the modified Response Evaluation Criteria in Solid Tumors (mRECIST), have been widely adopted for evaluating responses to locoregional therapies for hepatocellular carcinoma (HCC). We wished to establish the optimum maximum number of target lesions that need to be measured in enhancement estimations. METHODS: From a prospective registry in our institution we identified 160 consecutive patients who had at least two measurable HCCs of nodular type exceeding 10mm in diameter, and who initially underwent transarterial chemoembolization (TACE). Intra-patient and inter-method agreement on confirmed response status were evaluated based on a maximum of one, two, or three target lesions selected among the measurable lesions according to size, versus all baseline lesions. RESULTS: Per patient analyses showed that the most consistent response distribution under both EASL and mRECIST was obtained using two or three targets versus all measurable lesions. These features were maintained even in analyses of subgroups stratified according to size, distribution, and number of tumors. The kappa values of comparisons between using a maximum of two or three targets versus using all the lesions were near 1.0, significantly higher than those obtained under both criteria using just the largest tumor. Similar conclusions were obtained when either two or three targets were measured. CONCLUSIONS: Our data indicate that evaluating the largest two lesions is generally the most useful procedure for measuring TACE responses under both EASL and mRECIST.