OBJECTIVE: This study aims to evaluate the value of Kupffer phase imaging with Sonazoid-Contrast-Enhanced Ultrasound (CEUS) in differentiating atypical Hepatocellular Carcinoma (HCC) from Focal Nodular Hyperplasia (FNH), compared to the efficacy of Gadodiamide-Enhanced Magnetic Resonance Imaging (CEMRI). METHODS: We retrospectively reviewed a total of 56 focal liver lesions, comprising 36 atypical HCC and 20 FNH lesions, which were examined pre-operatively using both CEUS and CEMRI. Features were extracted from the images obtained from both modalities. The diagnostic performance of these features was evaluated using the Area Under the Receiver Operating Characteristic Curve (AUC). RESULTS: In the multivariate analysis, HBsAg-positive status (OR = 8.395, p = 0.021) and hypo-enhancement in the Kupffer phase (OR = 5.276, p = 0.042) were identified as independent predictors of atypical HCC. The specificity and sensitivity of HBsAg-positive for diagnosing atypical HCC are 65.0 % and 91.7 %, respectively. The specificity and sensitivity of hypo-enhancement in the Kupffer phase for diagnosing atypical HCC are 95.0 % and 63.9 %, respectively. Significantly, by integrating CEUS diagnostic characteristics to distinguish atypical HCC from FNH, we attained a specificity of 100.0 %, a sensitivity of 63.9 %, and a diagnostic accuracy of 76.8 %. Similarly, the combination of CEMRI diagnostic features resulted in a specificity of 100.0 %, a sensitivity of 47.2 %, and an overall diagnostic accuracy of 66.1 %. CEUS's diagnostic accuracy is superior to CEMRI and this difference is statistically significant (P <
0.05). CONCLUSION: Sonazoid-CEUS demonstrates significant clinical potential and is a viable tool for the differential diagnosis of atypical HCC and FNH.