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RATIONALE AND OBJECTIVE We aimed to determine the frequency and clinical significance of homogeneous renal masses measuring 21-39 Hounsfield units on contrast-enhanced computed tomography (CT). METHODS Subjects 40-69 years old undergoing portal-venous-phase contrast-enhanced abdominal CT from January 1, 2006 to December 31, 2010 with slice thickness ≤5 mm and no prior CT or magnetic resonance imaging were identified (n = 1387) for this institutional review board-approved retrospective cohort study. Images were manually reviewed by three radiologists in consensus to identify all circumscribed homogeneous renal masses (maximum of three per subject) ≥10 mm with a measured attenuation of 21-39 Hounsfield units. Exclusion criteria were known renal cancer or imaging performed for a renal indication. The primary outcome was retrospective characterization as a clinically significant mass, defined as a solid mass, a Bosniak IIF/III/IV mass, or extirpative therapy or metastatic renal cancer within 5 years' follow-up. RESULTS Eligible masses (n = 74) were found in 5% (63/1387) of subjects. Of those with a reference standard (n = 42), none (0% [95% CI: 0.0%-8.4%]) were determined to be clinically significant. CONCLUSION Incidental renal masses on contrast-enhanced CT that are homogeneous and display an attenuation of 21-39 Hounsfield units are uncommon in patients 40-69 years of age, unlikely to be clinically significant, and may not need further imaging evaluation. If these results can be replicated in an independent and larger population, the practical definition of a benign cyst on imaging may be able to be expanded.