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Introduction: Focal fatty sparing is a manifestation of fatty liver. Nodular focal fatty sparing of liver sometimes is a mimicker of malignant lesion, especially metastatic tumor. There are some case reports about this kind of tricks revealed by computed tomography (CT) and magnetic resonance imaging. However, few reports described nodular focal sparing of liver presenting an enhancement mode of hepatocellular carcinoma (HCC) in contrast-enhanced ultrasound (CEUS). Patient concerns: A 37-year-old male had a long history of alcohol abuse and hepatitis B virus infection. Routine blood examination showed an elevation of triglyceride, and tumor markers were unremarkable. Conventional ultrasound indicated a diffuse fatty liver with a hypoechoic nodular lesion. CEUS revealed hyperenhancement in arterial phase and washout in late phase of this hypoechoic lesion. Contrast-enhanced CT showed a similar enhancement mode of the mass with CEUS. Diagnosis: A clinical diagnosis of HCC was made. Then, liver resection was conducted. Postoperative histopathologic and immunohistochemical results of the lesion revealed no presence of tumor cells except for heterogeneous hepatic steatosis. So a final diagnosis of hepatic focal fatty sparing was determined. Interventions: Liver resection was conducted according to the clinical diagnosis of HCC. Outcomes: After general postoperative administration, the patient was told to discharge. Then, he had been undergoing regular serological tests and imaging examinations in our hospital for 39 months and found no manifestation of liver tumor. Conclusion: According to guidelines, it is typical that hepatic focal fatty change (FFC) presents a mode of persistent iso-enhancement in CEUS. However, atypical enhancement presence of FFC in imaging examinations may occur and lead to misdiagnosis, which calls for more attention.