Objective To investigate the application of contrast-enhanced ultrasound liver imaging reporting and data system version 2017 (CEUS LI-RADS v2017)for focal liver lesions in high-risk patients with alpha-fetoprotein(AFP)-negative. Methods From January 2018 to October 2021,134 focal liver lesions in 108 high-risk patients with AFP-negative who underwent contrast-enhanced ultrasound were retrospectively analyzed. Nodules were categorized according to the CEUS LI-RADS v2017.The reference standard was histopathology or contrast-enhanced imaging and follow-up.The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under the curve (AUC)of CEUS LI-RADS for HCC and other malignant tumors (OM) in AFP-negative patients were calculated. Results AFP-negative HCC was smaller than OM (P< 0.001). The positive predictive values of AFP-negative HCC in LR-5, LR-4, and LR-3 were88.37%,47.06% and 12.9%,respectively.The sensitivity, specificity,accuracy and AUC of LR-5 for AFP-negative HCC were 73.07%,93.90%,85.82% and 0.87,respectively.The sensitivity,specificity,positive predictive value, negative predictive value,accuracy and AUC of LR-M for OM were 90.91%,97.32%,86.96%,98.20%,96.27% and 0.94, respectively. Conclusions AFP-negative HCC was smaller than OM. CEUS Li-RADS v2017 shows high specificity and low sensitivity for AFP-negative HCC and good diagnostic efficiency for OM.