The objective was to evaluate whether the echogenicity of focal liver lesions (FLLs) on baseline gray-scale ultrasound (US) interferes with the diagnostic performance of contrast-enhanced US (CEUS) for small FLLs. Three-hundred and eighty-eight patients were examined by real-time CEUS using a sulfur hexafluoride-filled microbubble contrast agent. The images of 114 hyperechoic lesions, 30 isoechoic lesions and 244 hypoechoic lesions were reviewed by two blinded independent readers. A five-point confidence level was used to discriminate malignant from benign lesions, and specific diagnoses were made. The diagnostic performances were evaluated by receiver-operating characteristic (ROC) analysis. The diagnostic performances of CEUS on hyperechoic lesions in terms of the areas (Az) under the ROC curve were 0.987 (reader 1) and 0.981 (reader 2), and were 0.987 (reader 1) and 0.984 (reader 2) for iso- and hypoechoic lesions, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 87.0-95.9%, 93.1-100%, 88.6-100%, 70.0-97.1% and 90.0-95.1%, respectively. The echogenicity of FLLs on baseline gray-scale US does not appear to interfere with the diagnostic ability of CEUS for small FLLs.