Purpose: To evaluate the masking ability of computer-aided design/computer-aided manufacturing (CAD/CAM) zirconia-reinforced lithium silicate (ZLS) glass-ceramic under the different material configurations of thickness, translucency, and finishing protocol as well as significance of the color difference due to the manufacturer's one-firing protocol. Materials and methods: Ninety high-translucency (HT) and low-translucency (LT) ZLS glass-ceramic discs of different thicknesses (1.0, 1.5, and 2.0 mm) were evaluated as a monolithic structure with and without the use of a one-firing protocol. Disc samples were placed onto the substrates for measurement; a spectrophotometer measured the L*, a*, and b* color attributes of each specimen. ∆E value was calculated for determining color differences in tooth-colored substrate specimens (shade B1) compared with three darker backgrounds (shade C2, and two metal substrates - gold and silver). ∆E values were then compared against clinically acceptable (∆E = 5.5) and ideal (∆E = 2.6) thresholds. Color differences between the control and test groups were evaluated under different effects using a series of one-sided paired t tests (P 0.01). The 99% confidence interval (CI) for the true ∆E mean and P values are reported and discussed. A complementary regression analysis depicts the effect size of translucency and firing protocol. Results: Over C2, a 1-mm thickness demonstrated P 0.01 for the clinically acceptable threshold, whereas the ideal threshold was ensured only with P 0.01 under a 2-mm thickness. Over silver, only the clinically acceptable standard was met with P 0.01 under a 2-mm thickness. Over gold, a 1-mm thickness was clinically acceptable with P 0.01, and the ideal standard was met with P 0.01 under a 1.5-mm thickness. These results remained valid regardless of the firing protocol or translucency; however, significant (P 0.01) yet small-sized effects were found for translucency and firing protocol over gold, and for translucency over silver, through multiple regression analysis. Conclusions: To achieve ideal masking, the minimum thickness of CAD/CAM ZLS glass-ceramic should be 1.5 mm over a gold background, and 2 mm over a C2 background. The silver background did not achieve ideal masking in any situation. The one-firing protocol did not affect the final color and can be used to increase restoration strength. Keywords: color, spectrophotometry, computer-aided design/computer-aided manufacturing (CAD/CAM), zirconia-reinforced lithium silicate (ZLS) glass-ceramic, visual perception