Background: To prospectively establish and validate new diagnostic criterion (DC) for liverspecific contrast agents and further compared the diagnostic sensitivity and specificity with conventional DC. Methods: Institutional Review Board approved and written informed consent were obtained for this prospective study. Two board-certified reviewers established the reference standard as hepatocellular carcinoma (HCC), non-HCC lesions by using marks on all cross-sectional MR images. Another 2 abdominal radiologists independently performed the marked lesion observations using 5 different DCs, including DC-1: arterial phase hyperenhancement (APHE) and portal venous phase washout; DC-2: APHE and hepatobiliary phase (HBP) hypointensity; DC-3: APHE and diffusion-weighted imaging (DWI) hyperintensity; DC-4: HBP hypointensity and DWI hyperintensity; DC-5: HBP hypointensity, DWI hyperintensity and excluded these markedly T2 hyperintensity. Diagnostic performance of sensitivity, specificity, and accuracy for each imaging DC was calculated, per-lesion diagnostic sensitivity and specificity of imaging criteria were compared by using McNemars test. Results: A total of 215 patients were included (mean age 53.82 ± 11.24 years; range 24-82 years) with 265 hepatic nodules (175 HCCs and 90 non-HCCs). The DC-4 (93.71%; 164/175) and DC-5 (92.57%; 162/175) yielded the highest diagnostic sensitivity and was better than DC-1 (72.57%; 127/175), DC-2 (82.86%; 145/175), and DC-3 (82.29%; 144/175) (all p < 0.001). The specificity of DC-1 (94.44%;