PurposeTo systematically evaluate the potential of radiomics coupled with machine-learning algorithms to improve the predictive power for overall survival (OS) of renal cell carcinoma (RCC).MethodsA total of 689 RCC patients (281 in the training cohort, 225 in the validation cohort 1 and 183 in the validation cohort 2) who underwent preoperative contrast-enhanced CT and surgical treatment were recruited from three independent databases and one institution. 851 radiomics features were screened using machine-learning algorithm, including Random Forest and Lasso-COX Regression, to establish radiomics signature. The clinical and radiomics nomogram were built by multivariate COX regression. The models were further assessed by Time-dependent receiver operator characteristic, concordance index, calibration curve, clinical impact curve and decision curve analysis.ResultThe radiomics signature comprised 11 prognosis-related features and was significantly correlated with OS in the training and two validation cohorts (Hazard Ratios: 2.718 (2.246,3.291)). Based on radiomics signature, WHOISUP, SSIGN, TNM Stage and clinical score, the radiomics nomogram has been developed. Compared with the existing prognostic models, the AUCs of 5 years OS prediction of the radiomics nomogram were superior to the TNM, WHOISUP and SSIGN model in the training cohort (0.841 vs 0.734, 0.707, 0.644) and validation cohort2 (0.917 vs 0.707, 0.773, 0.771). Stratification analysis suggested that the sensitivity of some drugs and pathways in cancer were observed different for RCC patients with high-and low-radiomics scores.ConclusionThis study showed the application of contrast-enhanced CT-based radiomics in RCC patients, creating novel radiomics nomogram that could be used to predict OS. Radiomics provided incremental prognostic value to the existing models and significantly improved the predictive power. The radiomics nomogram might be helpful for clinicians to evaluate the benefit of surgery or adjuvant therapy and make individualized therapeutic regimens for patients with renal cell carcinoma.