Abstract Purpose Compared the impact of ultrasound contrast-enhanced fusion virtual navigation technology-guided microwave ablation (MWA) and standard MWA on the local tumor progression of hepatocellular carcinoma with unclear ultrasound images, to explore the utility of virtual navigation ultrasound contrast-enhanced imaging. Methods A retrospective analysis was conducted on clinical data from hepatocellular carcinoma patients admitted between June 2021 and August 2022, all of whom had liver lesions suggested by Computed Tomography (CT) or Magnetic Resonance (MR) but not visualized on 2D ultrasound. They underwent ultrasound contrast-enhanced fusion virtual navigation technology-guided microwave ablation and standard microwave ablation, and comparisons were made between the two groups in terms of general information, blood parameters, ultrasonic test, intraoperative indicators, ablation indicators, postoperative complications, recurrence indicators, local progression and long-term outcomes. Results There were no significant differences in blood parameters, postoperative complications, and disease-free survival between the two groups. (P > 0.05). The ultrasound contrast-enhanced fusion virtual navigation technology-guided microwave ablation group had significantly higher lesion detection rate, ablation efficacy, proportion of safe margin > 5 mm, recurrence time and complete ablation rate compared to the standard microwave ablation group, with significantly lower ablation time, recurrence rate and residual disease at 1-month compared to conventional ablation and significant differences in local progression (P