OBJECTIVE. The purpose of this study was to determine whether a single, uniform normalized iodine threshold reduces variability and enables reliable differentiation between vascular and nonvascular renal lesions independent of the dual-energy CT (DECT) platform used. MATERIALS AND METHODS. In this retrospective, HIPAA-compliant, institutional review board-approved study, 247 patients (156 men, 91 women; mean age ± SD, 67 ± 12 years old) with 263 renal lesions (193 nonvascular, 70 vascular) underwent unenhanced single- energy and contrast-enhanced DECT scans. One hundred and six nonvascular and 38 vascular lesions were scanned on two dual-source DECT (dsDECT) scanners, and 87 nonvascular and 32 vascular lesions were scanned on two rapid-kilovoltage-switching single-source DECT (rsDECT) scanners. Optimal absolute and normalized (to aorta) lesion iodine thresholds were determined for each platform type and for the entire cohort combined. RESULTS. Mean optimal absolute discriminant thresholds were 1.3 mg I/mL (95% CI, 1.2-1.9 mg I/mL), 1.6 mg I/mL (95% CI, 0.9-1.5 mg I/mL), and 1.5 mg I/mL (95% CI, 1.4- 1.7 mg I/mL) for dsDECT, rsDECT, and combined cohorts, respectively. Optimal normalized discriminant thresholds were 0.3 mg I/mL (95% CI, 0.2-0.4 mg I/mL) for both the dsDECT and rsDECT cohorts, and 0.3 mg I/mL (0.3-0.4 mg I/mL) for the combined cohort. The AUC, sensitivity, and specificity for the combined optimal normalized discriminant threshold of 0.3 mg I/mL was 0.96 (95% CI, 0.92-1.00), 0.93 (0.84-0.97), and 0.95 (0.91-0.98), respectively. Normalization resulted in decreased variability and better lesion separation (effect size, 1.77 vs 1.69, p < 0.0001). CONCLUSION. The optimal absolute discriminant threshold for evaluating renal lesions varies depending on the type of DECT platform, though this difference is not statistically significant. Variation can be reduced with a better separation of vascular and nonvascular lesions by normalizing iodine quantification to the aorta.