OBJECTIVE: To identify independent predictors of malignancy in Bosniak III (BIII) renal lesions and to build a prediction model based on readily identifiable clinical variables. METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study, radiology, and hospital information systems containing data from January 1, 1994, to August 31, 2009, were queried for adult patients (age >18 years) with surgically excised BIII lesions. Clinical variables and results of histopathology were noted. Univariate and multiple-variable logistic regression analyses were performed to identify potential predictors and to build a prediction model. Cross-validation was used to assess generalizability of the model's performance, as characterized by concordance (c) index. RESULTS: Of the 107 lesions in 101 patients, 59 were malignant and 48 benign. On univariate analyses, the strongest potential predictors of malignancy were African American race (P = .043), history of renal cell carcinoma (RCC; P = .026), coexisting BIII lesions (P = .032), coexisting Bosniak IV (BIV) lesions (P = .104), body mass index (BMI; P = .078), and lesion size (P <.001). A model with lesion size (odds ratio [OR] = 0.69; 95% confidence interval [CI] 0.58-0.82), history of RCC (9.02; CI 0.99-82.15), and BMI (OR 1.1; 95% CI 0.99-1.19) offered the best performance with a c-index after cross-validation of 0.719. Using an estimated probability of malignancy of >80%, the positive predictive value of the model is 92% (CI 78%-100%). CONCLUSION: Clinical risk factors offer modest but definite predictive ability for malignancy in BIII lesions. In particular, a prediction model encompassing lesion size, BMI, and history of RCC seems promising. Further refinements with possible inclusion of imaging biomarkers and validation on an independent dataset are desirable.