Abstract Background To assess whether intraoperative use of contrast-enhanced ultrasound (CEUS)-CT/MR image fusion can accurately evaluate ablative margin (AM) and guide supplementary ablation to improve AM after hepatocellular carcinoma (HCC) ablation. Methods Ninety-eight patients with 126 HCCs designated to undergo thermal ablation treatment were enrolled in this prospective study. CEUS-CT/MR image fusion was performed intraoperatively to evaluate whether 5-mm AM was covered by the ablative area. If possible, supplementary ablation was applied at the site of inadequate AM. The CEUS image quality, the time used for CEUS-CT/MR image fusion and the success rate of image fusion were recorded. Local tumor progression (LTP) was observed during follow-up. Clinical factors including AM were examined to identify risk factors for LTP. Results The success rate of image fusion was 96.2 % (126/131), and the duration required for image fusion was 4.9 ± 2.0 (3–13) min. The CEUS image quality was good in 36.1 % (53/147) and medium in 63.9 % (94/147) of the cases. By supplementary ablation, 21.8 % (12/55) of lesions with inadequate AMs became adequate AMs. During follow-up, there were 5 LTPs in lesions with inadequate AMs and 1 LTP in lesions with adequate AMs. Multivariate analysis showed that AM was the only independent risk factor for LTP (hazard ratio, 9.167; 95 % confidence interval, 1.070–78.571; p = 0.043). Conclusion CEUS-CT/MR image fusion is feasible for intraoperative use and can serve as an accurate method to evaluate AMs and guide supplementary ablation to lower inadequate AMs.