BACKGROUND: Incidentally detected small renal masses (SRMs) may be one of several benign or malignant tumor histologies, and are heterogeneous in oncologic potential. Renal mass biopsy can be used to determine the histology of SRMs. However, this invasive approach has significant limitations. Technetium-99m sestamibi single photon emission computed tomography/computed tomography (Tc-sestamibi SPECT/CT) is a promising imaging tool that can aid in identifying benign renal oncocytomas and hybrid oncocytic/chromophobe tumors. OBJECTIVE: To evaluate the clinical and economic value of Tc-sestamibi SPECT/CT in guiding the management of SRMs. DESIGN, SETTING, AND PARTICIPANTS: We developed a decision analysis model to estimate the costs and health outcomes of competing management strategies for a healthy 65-yr-old patient with an asymptomatic SRM. INTERVENTION: Empiric surgery (reference); real-world clinical practice (RWCP) consisting of empiric surgery, thermal ablation, and active surveillance (alternative reference); renal mass biopsy (option 1); Tc-sestamibi SPECT/CT (option 2); and Tc-sestamibi SPECT/CT followed by biopsy to confirm benign SRMs (option 3). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed lifetime health utilities, measured in quality-adjusted life years (QALYs), and direct medical costs from a health payer perspective. We calculated the incremental cost-effectiveness ratio (ICER) for options 1-3 versus the reference and alternative reference arms, with a willingness-to-pay threshold of $50 000/QALY. Univariate, multivariate, and probabilistic sensitivity analyses were performed. RESULTS AND LIMITATIONS: Option 3 had a very low risk of untreated malignant tumors (0.2%, vs 2.1% for option 1, 4.2% for option 2, and 0% for empiric surgery) and the highest probability of leaving benign tumors untreated (84.4%, vs 53.9% for option 1, 51.7% for option 2, and 0% for empiric surgery). Option 3 dominated empiric surgery and options 1 and 2 (ie, lower costs and higher QALYs). Compared with RWCP, options 1-3 were all cost effective; option 3 had the lowest ICER of $18 821/QALY. These findings were robust to alternative input values. Study limitations included data uncertainties and a limited number of centers from which Tc-sestamibi SPECT/CT performance data were collected. CONCLUSIONS: Tc-sestamibi SPECT/CT followed by confirmatory biopsy helps avoid surgery for benign SRMs, minimizes untreated malignant SRMs, and is cost effective compared with existing strategies. PATIENT SUMMARY: Our research suggests that by using a noninvasive imaging test, known as technetium-99m sestamibi single photon emission computed tomography/computed tomography, to diagnose small renal masses, urologists may avoid unnecessary surgery for benign tumors and minimize the risk of leaving a malignant tumor untreated. Moreover, the use of this strategy to diagnose small renal masses is cost effective for the health care system.