Objective To explore the preoperative predictive efficacy of multimodal ultrasound based on microflow imaging(MFI) in Glypican-3(GPC-3) in hepatocellular carcinoma(HCC). Methods The general data and ultrasonographic data of patients with HCC confirmed by histopathology and hepatectomy from January 2019 to June 2023 were analyzed retrospectively. According to the gold standard of postoperative pathology, the patients were divided into GPC-3 positive group and GPC-3 negative group. Through analyze the correlation between multimodal ultrasound features and GPC-3, to determine the independent predictors of GPC-3, and to further analyze the preoperative predictive efficiency of Two-dimensional ultrasound(2D-US), contrast-enhanced ultrasound(CEUS) and microflow imaging(MFI) for GPC-3 of HCC. Results A total of 102 patients were enrolled in this study, including 60 GPC-3 positive patients(58.8%) and 42 GPC-3 negative patients(41.2%). Through univariate and multivariate analysis, it was found that there were significant differences in diameter(95%CI: 1.080-7.741, P = 0.034), start washout time(95%CI: 0.105-0.694, P = 0.007) and CEUS-MFI(95%CI: 1.180-4.553, P = 0.015) between the two groups, which were independent predictors of GPC-3 positive occurrence. The prediction efficiency of multimodal ultrasound combined with GPC-3 for HCC is better than that of single mode(P<0.05). Conclusion The feasibility of multimodal ultrasound in predicting GPC-3 of HCC before operation is confirmed.