Computer-aided design and computer-aided manufacturing (CAD-CAM) monochromatic restorative materials are gaining popularity because of their convenience and efficiency. However, studies that quantitatively analyzed color change associated with thickness and surface roughness are sparse. The purpose of this in vitro study was to quantitatively evaluate the color of 6 CAD-CAM monochromatic materials of different thickness and surface roughness using the CIELab color system. A total of 150 12×12-mm square specimens of 6 different CAD-CAM monochromatic materials (VITA Enamic HT [VE], IPS e.max CAD HT [LS], LAVA Ultimate HT [LU], Telio CAD HT [TE], VITA Suprinity HT [VS], and Celtra Duo HT [CD]) in shade A2 and 5 different thicknesses (from 0.5mm to 2.5mm, with 0.5-mm increments) were fabricated (n=5). After 3 different surface treatments (polished, roughened by SiC P800-grit, and P300-grit), CIELab color parameters (L*, a* and b*) were measured using a spectrophotometer (VITA Easyshade V), and surface roughness was measured with a profilometer (VK-X200). Color variation was quantified by ΔE00 and 50:50% acceptability and perceptibly thresholds. Data analyses were performed using MANOVA, 2-way ANOVA, post hoc Tukey-Kramer test, and the 1-sample t test (α=.05). The L*, a*, and b* of the monochromatic specimens were significantly influenced by material type, thickness, and surface roughness (P<.001). An overall increase in the L* (from 61.90 to 82.2), a* (from -4.22 to 1.16), and b* (from 5.48 to 43.22) of the specimens was observed with increased thickness. The roughened specimens exhibited lower L* and higher a* and b* than the polished ones (P<.001). The use of P300-grit for roughening resulted in greater ΔE00 compared with P800-grit (P<.001). As thickness decreased or surface roughness increased, the ΔE00 increased and exceeded the acceptability and perceptibly thresholds for color difference. Material type, thickness, and surface roughness were major factors affecting the color of CAD-CAM monochromatic materials. Variations in thickness of 0.5mm or more, as well as roughening treatments, may lead to clinically unacceptable color changes.