The objective of this study was to investigate the potential usefulness of contrast-enhanced power Doppler ultrasonography in the differentiation of benign and malignant cystic renal lesions. Our study group was limited to patients who had complex cystic renal lesions of uncertain malignancy at screening ultrasonography. During the previous 6 months, 485 patients have been referred to ultrasonography for evaluation of renal cystic lesions, but only 13 patients participated in this study. Focusing on tumor vascularity in the intracystic septa or solid component, we analyzed power Doppler sonographic images before and after intravenous injection of contrast agent and compared them with contrast-enhanced CT scans or MR images and pathologic results. The visualization of vascularity was best on contrast-enhanced power Doppler sonography (n = 7). The use of contrast agent with power Doppler sonography showed improved diagnostic accuracy (77%) that was superior to non-contrast-enhanced power Doppler sonography or contrast-enhanced CT. In conclusion, contrast-enhanced power Doppler sonography provides better visualization of tumor vascularity in complicated cystic renal lesions than other imaging modalities, leading to more exact differential diagnosis. We therefore expect that this imaging modality might be very useful in differential diagnosis of problematic cystic renal lesions, benign or malignant.