Ultra-translucent multilayered zirconia restorations fabricated using computer-aided design and computer-aided manufacturing (CAD/CAM) technology have recently gained popularity. Their esthetic appeal is crucially dependent on the color accuracy, influenced by prosthesis thickness and multilayer composition due to CAD/CAM milling positions. This study comprehensively investigated how these two factors impacted color accuracy, thereby enhancing our understanding of color outcomes. One hundred monolithic multilayer zirconia specimens with 10 × 10 mm square shape were milled in four different positions and five different thicknesses (1.0, 1.5, 2.0, 2.5, and 3.0 mm). The specimens were placed on an A3 shade resin composite substrate, and CIELAB values (L ∗, a ∗, and b ∗) were measured using a spectrophotometer. Delta E (ΔE) values were calculated to quantify the color differences between the specimens and the A3 VITA classical shade tab and compared with the perceptibility and acceptability thresholds of ΔE = 1.2 and 2.7, respectively. Pearson correlation, two-way ANOVA, and Tukey multiple comparisons (α = 0.05) were performed. The proportion of the dentin layer was positively correlated with the a ∗ and b ∗ values, while specimen thickness was positively correlated with the a ∗ value and negatively correlated with the L ∗ and b ∗ values. Significant difference in ΔE value due to different CAD/CAM positions was not observed within the same specimen thickness. Perceptible color differences were observed in specimens with thicknesses greater than 1 mm, while specimens with 1 mm thickness fell within the clinically acceptable range. Highest ΔE value was found in the specimen with 1 mm thickness. Different compositions of multilayers in the final restoration due to different CAD/CAM positions do not significantly affect the color appearance of ultra-translucent multilayer zirconia, with color only influenced by specimen thickness.
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