The study was aimed at evaluating the diagnostic performance of contrast-enhanced ultrasound (CEUS) in characterizing complex cystic focal liver lesions (FLLs). Sixty-seven complex cystic FLLs in 65 patients were examined with conventional ultrasound (US) and real-time CEUS. The US and CEUS images were reviewed by a resident radiologist and a staff radiologist independently. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance, and the interobserver agreement was analysed. The results showed that complete non-enhancement throughout three phases of CEUS or sustained enhancement in the portal and late phases were exhibited in most benign lesions. Conversely, hypo-enhancement in the late phase was seen in all malignancies. After ROC analysis, the areas (Az) under the ROC curve were 0.774 at US versus 0.922 at CEUS (P=0.047) by the resident radiologist, and 0.917 versus 0.935 (P=0.38) by the staff radiologist. A significant difference in Az between the resident and the staff radiologists was found for US (0.774 versus 0.917, P=0.044), whereas not found for CEUS (0.922 versus 0.935, P=0.42). Interobserver agreement was improved after CEUS (kappa=0.325 at US versus kappa=0.774 at CEUS). Real-time CEUS improves the capability of discrimination between benign and malignant complex cystic FLLs, especially for the resident radiologist.