To identify the risk factors for predicting the malignant progression of LR-3/4 observations on the baseline and contrast-enhanced ultrasound (CEUS).In total, 245 liver nodules assigned to LR-3/4 in 192 patients from January 2010 to December 2016 were followed up by baseline US and CEUS. The differences in the rate and time of progression to hepatocellular carcinoma (HCC) among subcategories (defined as P1-P7) of LR-3/4 in CEUS Liver Imaging Reporting and Data System (LI-RADS) were analyzed. The risk factors to predict progression to HCC were analyzed by univariate and multivariate Cox proportional hazard model analysis.A total of 40.3% of LR-3 nodules and 78.9% of LR-4 nodules eventually progressed to HCC. The cumulative incidence of progression was significantly higher for LR-4 than LR-3 (p < 0.001). The rate of progression was 81.2% in nodules with arterial phase hyperenhancement (APHE), 64.7% in nodules with late and mild washout, and 100% in nodules with both characteristics. The overall progression rate and median progression time of subcategory P1 nodules (LR-3a) were lower (38.0% vs. 47.6-100.0%) and later (25.1 months vs. 2.0-16.3 months) than those of other subcategories. The cumulative incidence of progression of LR-3a (P1), LR-3b (P2/3/4), and LR-4 (P5/6/7) categories were 38.0%, 52.9%, and 78.9%. The risk factors of HCC progression were Visualization score B/C, CEUS characteristics (APHE, washout), LR-4 classification, echo changes, and definite growth.CEUS is a useful surveillance tool for nodules at risk of HCC. CEUS characteristics, LI-RADS classification, and changes in nodules provide useful information for the progress of LR-3/4 nodules.CEUS characteristics, LI-RADS classification, and nodule changes provide important predictions for LR-3/4 nodule progression to HCC, which may stratify the risk of malignant progression to provide a more optimized and refined, more cost-effective, and time-efficient management strategy for patients.• CEUS is a useful surveillance tool for nodules at risk of HCC, CEUS LI-RADS successfully stratified the risks that progress to HCC. • CEUS characteristics, LI-RADS classification, and changes in nodules can provide important information on the progression of LR-3/4 nodules, which may be helpful for a more optimized and refined management strategy.© 2023. The Author(s), under exclusive licence to European Society of Radiology.