Purpose Dual-layer spectral computed tomography (DLSCT) is a novel CT platform of dual-energy CT. Virtual non-contrast (VNC) imaging theoretically resembles true non-contrast (TNC) imaging by subtracting iodine attenuation from post-contrast data. We aimed to compare qualitative and quantitative datasets between TNC and VNC in patients with upper aerodigestive tract cancer (UATC) and to evaluate the potential radiation dose reduction obtained by omitting the TNC phase. Material and methods The study included 61 patients with UATC who underwent DLSCT. The CT protocol included TNC and post-contrast phases. The VNC images were reconstructed from the post-contrast phase. The differences of mean CT attenuation values, imaging noise, and image quality for TNC and VNC images were compared. The effective radiation doses of a biphasic TNC and post-contrast CT protocol were compared with a single-phase protocol (post-contrast CT with VNC reconstruction). Results There were a total of 732 ROIs from TNC and VNC. There was no statistical difference in the mean CT attenuation values between TNC and VNC images for all tissue types ( p = 0.09-0.44), except for the buccal fat pad. Overall, 85.3% of cases revealed a difference of less than 10 HU. There was no significant difference in mean imaging noise ( p = 0.5455) and image quality ( p = 0.3214) between 2 acquisitions. All VNC images had acceptable quality for diagnostic purposes. The potential dose reduction by omitting the TNC was 49.5 ± 3.5%. Conclusion VNC could replace TNC images in patients with UATC, with good image quality and the advantage of radiation dose reduction.