AIM To clarify the value of gray-scale ultrasound (US) combined with contrast-enhanced US (CEUS) with perflubutane in diagnosing early hepatocellular carcinoma (HCC). METHODS A total of 57 surgically resected, well differentiated HCCs were analyzed. Hepatocellular carcinomas were macroscopically diagnosed as vaguely nodular or distinctly nodular types, which correspond to early HCC or progressed HCC, respectively. Gray-scale US findings were evaluated in terms of shape (round or roundish, or irregular), border and contour (well-defined and smooth, or poorly defined), and intratumor echo levels (hyper, hypo, iso, heterogeneous, or mosaic). Contrast-enhanced US findings were evaluated during the arterial phase (vascularity [finely homogeneous, dendritic, or chaotic] and perfusion enhancement [homogeneous or heterogeneous]), portal phase (presence or absence of washout), and post-vascular phase (echo intensity level [defect, incomplete defect, or iso-enhancing]). RESULTS Eighteen HCCs were categorized as early HCCs and the remaining 39 were categorized as progressed HCCs. Receiver operating characteristic curve analysis for the diagnosis of early HCC yielded area under the receiver operating characteristic curve (Az ) values for border and contour on gray-scale US and echo intensity level in the CEUS post-vascular phase of 0.782 and 0.828, respectively. Multiple logistic regression analysis also indicated that both of these gray-scale US and CEUS findings were independently associated with early HCC. The Az value for the combination of border and contour and echo intensity for the diagnosis of early HCC was 0.907, corresponding to a high diagnostic value. CONCLUSION The combination of gray-scale US and CEUS can provide high-quality imaging assessment for diagnosing early HCC.