© 2017 Wolters Kluwer Health, Inc. All rights reserved. Purpose This study investigates whether the addition of preoperative 99mTc-MIBI SPECT/CT can increase the degree of diagnostic confidence in the differentiation of benign from malignant enhancing renal masses. Patients and Methods Patients were recruited as part of an institutional review board-approved prospective clinical trial. Forty-eight patients with clinical stage T1 solid renal masses who underwent a 99mTc-MIBI SPECT/CT before partial or radical nephrectomy were evaluated. Conventional CT and MRI, which were approximately performed within 8 weeks before 99mTc-MIBI, were retrospectively retrieved. Based on a 5-point scale (1 = definitely benign, 5 = definitely malignant), 2 blinded readers recorded their degree of confidence for each lesion using conventional imaging before and after reviewing the 99mTc-MIBI uptake ratios. Surgical pathology was considered as the reference standard. Results Additional review of 99mTc-MIBI SPECT/CT uptake ratios increased diagnostic confidence in the differentiation of solid renal masses in 14/48 lesions (29.2%). In 9 lesions, the addition of 99mTc-MIBI changed the initial confidence levels of malignancy toward benign diagnosis. Postsurgical pathology confirmed the diagnosis of benign histology (oncocytoma/hybrid oncocytic-chromophobe tumors) in 7 and chromophobe renal cell carcinoma (behave as indolent) in 2 of these lesions. 99mTc-MIBI increased the confidence level toward malignancy in 5 cases; all were confirmed as RCC on surgical pathology. The area under the receiver operative characteristic curve was 0.60 for conventional imaging alone and 0.85 after reviewing 99mTc-MIBI (P for difference = 0.03). Conclusions Preoperative 99mTc-MIBI SPECT/CT enhances the performance of conventional imaging, improving the characterization of benign histologies and lowering the possibility of misclassification.