Purpose To investigate whether dual-energy multidetector row computed tomographic (CT) imaging with iodine quantification is able to distinguish between clear cell and papillary renal cell carcinoma (RCC) subtypes. Materials and Methods In this retrospective, HIPAA-compliant, institutional review board-approved study, 88 patients (57 men, 31 women) with diagnosis of either clear cell or papillary RCC at pathologic analysis, who underwent contrast material-enhanced dual-energy nephrographic phase study between December 2007 and June 2013, were included. Five readers, blinded to pathologic diagnosis, independently evaluated all cases by determining the lesion iodine concentration on color-coded iodine maps. The receiving operating characteristic curve analysis was adopted to estimate the optimal threshold for discriminating between clear cell and papillary RCC, and results were validated by using a leave-one-out cross-validation. Interobserver agreement was assessed by using an intraclass correlation coefficient. The correlation between tumor iodine concentration and tumor grade was investigated. Results A tumor iodine concentration of 0.9 mg/mL represented the optimal threshold to discriminate between clear cell and papillary RCC, and it yielded the following: sensitivity, 98.2% (987 of 1005 [95% confidence interval: 97.7%, 98.7%]); specificity, 86.3% (272 of 315 [95% confidence interval: 85.0%, 87.7%]); positive predictive value, 95.8% (987 of 1030 [95% confidence interval: 95.0%, 96.6%]); negative predictive value, 93.7% (272 of 290 [95% confidence interval: 92.8%, 94.7%]); overall accuracy of 95.3% (1259 of 1320 [95% confidence interval: 94.6%, 96.2%]), with an area under the curve of 0.923 (95% confidence interval: 0.913, 0.933). An excellent agreement was found among the five readers in measured tumor iodine concentration (intraclass correlation coefficient, 0.9990 [95% confidence interval: 0. 9987, 0.9993). A significant correlation was found between tumor iodine concentration and tumor grade for both clear cell (τ = 0.85; P < .001) and papillary RCC (τ = 0.53; P < .001). Conclusion Dual-energy multidetector CT with iodine quantification can be used to distinguish between clear cell and papillary RCC, and it provides insights regarding the tumor grade. © RSNA, 2014.