To test the hypothesis that qualitative and quantitative features of contrast material-enhanced ultrasonography (US) can be used to differentiate benign from malignant small renal masses. This is an institutional review board approved, HIPAA-compliant prospective study with written informed consent. Patients with histologically characterized solid small renal masses, excluding lipid-rich angiomyolipomas, underwent qualitative contrast-enhanced US with a combination of three different US machines. A subgroup of patients underwent quantitative contrast-enhanced US. Patients received a bolus injection of 0.2 mL of contrast material for qualitative and quantitative evaluations and were followed for 3 minutes. Two radiologists independently reviewed videotaped qualitative contrast-enhanced US examinations and were blinded to the final diagnoses. Features that were evaluated included lesion vascularity relative to the adjacent cortex in the arterial phase, the presence of a capsule, homogeneity, the pattern of vascularity, and washout. One radiologist separately reviewed a subset of contrast-enhanced US examinations that were performed with all three machines. Parameters of a first-pass time intensity curve were calculated for quantitative analysis. The Mann-Whitney test was used for quantitative parameters, the χ(2) or Fisher exact test was used for qualitative parameters, and κ statistics and Fleiss methodology were used to determine interobserver and intermachine agreement. The study population consisted of 91 patients (35 women and 56 men) with 94 lesions. The mean age was 62 years ± 14 (range, 21-91). Three patients had two lesions each, which were evaluated at two different sessions. There were 26 benign small renal masses (including 18 oncocytomas, seven lipid-poor angiomyolipomas, and one hemangioblastoma) and 68 malignant masses (including 41 clear cell, 20 papillary, and seven chromophobe renal cell carcinomas [RCCs[) that were 1.1-4.0 cm in diameter (mean, 2.7 cm ± 0.9). All patients underwent contrast-enhanced US on the same one machine, and 68 patients were imaged on all three machines. Vascularity was present in all lesions (n = 94) at contrast-enhanced US. Lesion hypovascularity relative to the adjacent cortex in the arterial phase was seen in only malignant lesions by both reviewers; reviewer 1 saw hypovascularity in 24 of 94 lesions (P = .0001), and reviewer 2 saw hypovascularity in 21 of 94 lesions (P = .0006), for a specificity of 100% (95% confidence interval [CI]: 84, 100). This feature had κ values of 0.91 (95%CI: 0.82, 1.00) between the two reviewers and 0.85 (95% CI: 0.72, 0.99) between the three machines. Eighteen of 20 papillary RCCs were hypovascular. Quantitative parameters of area under the receiver operating characteristics curve, peak intensity, wash-in slope of 10%-90% and 5%-45%, and washout slope of 100%-10% and 50%-10% were significantly higher in malignant renal masses (P = .018, P = .002, P = .036, P = .016, P = .001, and P = .005, respectively) than in benign lesions. Excluding lipid-rich angiomyolipoma, hypovascularity-which has high interobserver and intermachine agreement-of solid small renal masses relative to the cortex in the arterial phase has 100% specificity (95% CI: 84, 100) for detecting malignancy, most often papillary RCC.