Objectives <p>The purpose of this in vitro study was to investigate the effect of zirconia color, thickness, and moisture condition on color difference values (ΔE₀₀) using two shade guides.</p> Materials and methods <p>Forty-two zirconia specimens were divided into three color groups: A1, A2, and A3 (<i>n</i> = 14 each). Each color group comprised two thickness groups (1.5 and 2.0&#xa0;mm; <i>n</i> = 7 each) and underwent testing over 50&#xa0;V anodization titanium background specimen (<i>n</i> = 7) in wet and dry conditions, yielding 12 experimental groups. All the specimens were examined using a spectrophotometer and compared with the two control groups (zirconia and vita shade guides, <i>n</i> = 1) to establish ΔE₀₀. The ΔE₀₀¹ (zirconia shade guide) and ΔE₀₀² (vita shade guide) values were calculated for the first and second hypotheses, respectively. ΔE₀₀ values = 1.8 were considered 50% clinically acceptable threshold (AT). The data collected were statistically analyzed using analysis of variance and appropriate post-hoc tests (<i>P</i> = .05).</p> Results <p>The wet/dry condition, zirconia color, and thickness significantly affected the observed ΔE₀₀ (P &lt;.05) for both shade guides. The dry condition using 1.5- and 2.0-mm zirconia revealed values same as or greater than the estimated mean when compared with the wet condition (P &lt; .05) for both shade guides. In contrast to the vita shade guide, all the mean and 95% confidence interval (CI) values of ΔE₀₀¹were below 50% AT, except 1.5-mm zirconia with A1 and A3 shades in dry condition.</p> Conclusions <p>The use of a 1.5-mm and A1–A3 shade zirconia over yellow-anodized titanium potentially results in acceptable color matching with 95% CIs using a combination of wet condition and zirconia shade guide.</p>