© 2022 Editorial Council for the Journal of Prosthetic DentistryStatement of problem: Knowledge on the effect of multiple firings on surface roughness and the flexural strength of different types of monolithic computer-aided design and computer-aided manufacturing (CAD-CAM) ceramics is limited. Purpose: The purpose of this in vitro study was to evaluate the effect of multiple firings on the surface roughness and flexural strength of 4 different CAD-CAM ceramics after thermocycling. Material and methods: Four different CAD-CAM ceramics (Lava All Zirconia 3-mol yttria tetragonal zirconia polycrystal [3-YTZP] [Z], VITA SUPRINITY [S], IPS e.max CAD [EX], IPS Empress CAD [E]) (n=33) were wet-sectioned to form rectangular 18×4×1.2-mm specimens. After glaze application, the specimens were divided into 3 subgroups according to the number of firings (1, 2, and 4) (n=11). The specimens were thermocycled (10 000 cycles), and surface roughness and flexural strength values were measured (n=10). One additional specimen from each group was analyzed by using scanning electron microscopy (SEM). Data were analyzed by 2-way analysis of variance (ANOVA) and the Tukey honestly significance difference (HSD) test (α=.05). Results: According to the 2-way ANOVA, the material, number of firings, and the interaction between the material and number of firings affected the surface roughness (P<.001). For flexural strength, material (P<.001) and number of firings (P<.039) were found significant. Multiple firings (2 or 4 firings) affected the surface roughness of E (P<.001). Regardless of the number of firings, the Z material had the highest flexural strength (P<.001). Four firings affected the flexural strength values only for the Z material (P≤.005). Conclusions: CAD-CAM ceramic type affected the surface roughness and flexural strength values. The surface roughness of E was lower when fired 2 or 4 times than when fired once. The flexural strength of Z was lower when fired 4 times than when fired once.