Background The development of an accurate, practical, noninvasive, and widely available diagnostic approach to characterize lipid-poor adrenal lesions (greater than 10 HU at unenhanced CT) remains an ongoing demand. Purpose To investigate whether combined assessment of unenhanced and portal venous phase CT allows for the differentiation of lipid-poor adrenal adenomas from nonadenomas. Materials and Methods Patients with lipid-poor adrenal lesions who underwent unenhanced and portal venous phase CT with a single-energy scanner between January 2016 and March 2020 were identified retrospectively. For each lesion, the unenhanced and contrast-enhanced attenuation were measured; the absolute enhancement (contrast-enhanced minus unenhanced attenuation [HU]) and relative enhancement ratio ([absolute enhancement divided by unenhanced attenuation] × 100%) were calculated. The sensitivity achieved at 95% specificity to distinguish adenomas from nonadenomas was determined with receiver operating characteristic curve analysis and compared among parameters with use of the McNemar test. Results A total of 220 patients (mean age ± standard deviation, 66 years ± 12; 134 men) with 131 lipid-poor adenomas and 89 nonadenomas were analyzed. The sensitivity (achieved at 95% specificity) of the relative enhancement ratio (86% [113 of 131 adenomas; 95% CI: 79, 92] at a threshold of >210%) was higher than that of unenhanced attenuation (50% [66 of 131 adenomas; 95% CI: 42, 59] at a threshold of ≤21 HU), contrast-enhanced attenuation (3% [four of 131 adenomas; 95% CI: 1, 8] at a threshold of >120 HU), and absolute enhancement (24% [32 of 131 adenomas; 95% CI: 17, 33] at a threshold of >74 HU; all P < .001). The sensitivities of the relative enhancement ratio were 100% (58 of 58 adenomas; 95% CI: 94, 100), 83% (52 of 63 adenomas; 95% CI: 71, 91), and 30% (three of 10 adenomas; 95% CI: 7, 65) for adenomas measuring unenhanced attenuation of more than 10 HU up to 20 HU, 21-30 HU, and more than 30 HU, respectively. Conclusion A relative enhancement ratio threshold of greater than 210%, measured at unenhanced and portal venous phase CT, accurately differentiated lipid-poor adenomas from nonadenomas, particularly for lesions with unenhanced attenuation of 10-30 HU. © RSNA, 2021 Online supplemental material is available for this article.