BACKGROUND. Prior studies have provided mixed results for the ability to replace true unenhanced (TUE) images with virtual unenhanced (VUE) images when characterizing renal lesions by dual-energy CT (DECT). Detector-based dual-layer DECT (dlDECT) systems may optimize performance of VUE images for this purpose. OBJECTIVE. The purpose of this article was to compare dual-phase dlDECT examinations evaluated using VUE and TUE images in differentiating cystic and solid renal masses. METHODS. This retrospective study included 110 patients (mean age, 64.3 ± 11.8 years; 46 women, 64 men) who underwent renal-mass protocol dlDECT between July 2018 and February 2022. TUE, VUE, and nephrographic phase image sets were reconstructed. Lesions were diagnosed as solid masses by histopathology or MRI. Lesions were diagnosed as cysts by composite criteria reflecting findings from MRI, ultrasound, and the TUE and nephrographic phase images of the dlDECT examinations. One radiologist measured lesions' attenuation on all dlDECT image sets. Lesion characterization was compared between use of VUE and TUE images, including when considering enhancement of 20 HU or greater to indicate presence of a solid mass. RESULTS. The analysis included 219 lesions (33 solid masses; 186 cysts [132 simple, 20 septate, 34 hyperattenuating]). TUE and VUE attenuation were significantly different for solid masses (33.4 ± 7.1 HU vs 35.4 ± 8.6 HU, p = .002), simple cysts (10.8 ± 5.6 HU vs 7.1 ± 8.1 HU, p < .001), and hyperattenuating cysts (56.3 ± 21.0 HU vs 47.6 ± 16.3 HU, p < .001), but not septate cysts (13.6 ± 8.1 HU vs 14.0 ± 6.8 HU, p = .79). Frequency of enhancement 20 HU or greater when using TUE and VUE images was 90.9% and 90.9% in solid masses, 0.0% and 9.1% in simple cysts, 15.0% and 10.0% in septate cysts, and 11.8% and 38.2% in hyperattenuating cysts. All solid lesions were concordant in terms of enhancement 20 HU or greater when using TUE and VUE images. Twelve simple cysts and nine hyperattenuating cysts showed enhancement of 20 HU or greater when using VUE but not TUE images. CONCLUSION. Use of VUE images reliably detected enhancement in solid masses. However, VUE images underestimated attenuation of simple and hyperattenuating cysts, leading to false-positive findings of enhancement by such lesions. CLINICAL IMPACT. The findings do not support replacement of TUE acquisitions with VUE images when characterizing renal lesions by dlDECT.