Background: To evaluate the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) in characterizing between malignant and benign renal lesions confirmed by histological examination. Methods: Overall, 110 patients, for a total of 118 renal masses previously identified at CT and MRI underwent CEUS. An expert radiologist evaluated morphological, qualitative and quantitative parameters. Acquired data were analyzed to assess the value of each parameter to differentiate between malignant and benign lesions. Results: Histological results of 118 renal masses showed 88 (75%) malignant lesions and 30 (25%) benign lesions. Among morphological features, inhomogeneous echogenicity was the best predictor of malignancy depicting a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 76%, 76%, 88% and 57%, respectively. Among qualitative parameters, the most reliable parameter was the presence of pseudo-capsule. Here, sensitivity, specificity, positive PPV and NPV were 85%, 86%, 94% and 71%, respectively. Among quantitative parameters, the most reliable parameters were peak intensity (PI) and the area under the (AUC) with sensitivity, specificity, PPV and NPV values of 94%, 92%, 96% and 87% and 99%, 92%, 97% and 97%, respectively. Finally, the most reliable parameters were combined to distinguish between benign and malignant lesions. The best combination obtained was restricted to CEUS parameters (PI and AUC). Here, sensitivity, specificity, PPV, NPV and accuracy rate were 93%, 100%, 100%, 83% and 93%, respectively. Conclusions: CEUS increases the US accuracy to discriminate between benign and malignant renal lesions.