【Objective】To explore the evaluation value of ultrasomics based on contrast- enhanced ultrasound （CEUS）imaging in the therapy response of microRNA-122（miR-122）in hepatocellular carcinoma（HCC）.【Method】 Mice bearing subcutaneous HCC xenografts were injected intratumorally with microRNA-122 mimics（miR-122 mimics） and negative control mimics（NC mimics）in treatment group（n=6）and control group（n=6），respectively. The injec? tions were performed every 3 days for five times. Before each injection，two-dimension ultrasound（2D-US）imaging was performed. At 24 h after the last injection，2D-US and CEUS images of tumors were acquired，and then mice scarified for tumor miR-122 expression analysis by qRT-PCR. To evaluate the therapy response by RECIST，tumor volumes were mea?sured based on each 2D-US image. To analyze the tumor perfusion by mRECIST，perfusion parameters（maximum of intensity，rise time，time to peak，mean transit time，quality of fit）were analyzed off-line based on dynamic CEUS videos using SonoLiver ? software. For ultrasomics，CEUS images at 10，30，60，90 second were used for features extraction， respectively. The corresponding ultrasomics formulas were built to evaluate the therapy response for miR-122.【Result】 The tumors treated with miR-122 mimics resulted in a（763±60）folds increase in miR-122 levels compared to the tumors in control group（P<0.05）. Effectively therapeutic response evaluated by tumor sizes change was detected after the third injection（P<0.05）. For assessment using mRECIST，all the parameters of treatment group did not show significant difference from the ones of control group（P>0.05）. Analysis using ultrasomics fail to detect different features of the static images of CEUS at 10 s，and models can be successfully built based on the rest of the three phases of CEUS images. The ultrasomics Scores between control group and treatment group were statistically different（P<0.05）. The ultrasomics score at 30s were significantly lower than those at 60 s and 90 s，while there was no statistical difference between scores at 60 s and 90 s.【Conclusion】Ultrasomics analysis based on CEUS imaging is a useful method in evaluating the therapy response of miR-122 in HCC，and showed greater value than dynamic perfusion parameter.