© 2022 Editorial Council for The Journal of Prosthetic DentistryStatement of problem: Previous studies have shown the susceptibility of dental ceramics to degradation when subjected to certain media. However, knowledge on the effect of repeated firings and thermocycling on the ion elution of computer-aided design and computer-aided manufacturing (CAD-CAM) ceramics is lacking. Purpose: The purpose of this in vitro study was to compare the effect of repeated firings on the ion elution of CAD-CAM materials before and after thermocycling. Material and methods: Bar-shaped specimens were prepared from 4 different CAD-CAM materials (monolithic zirconia [Z], zirconia-reinforced lithium silicate glass-ceramic [S], lithium disilicate glass-ceramic [EX], and leucite-reinforced glass-ceramic [E]) and divided into 3 groups according to the number of repeated glaze firings (1 firing [1F], 2 firings [2F], and 4 firings [4F]). Specimens were placed into deionized water (pH 7.4) and stored at 37 °C for 168 hours. Inductively coupled plasma-optic emission spectrophotometry (ICP-OES) was used to measure the baseline values of the eluted ions in immersion. The specimens were then subjected to thermocycling. Then, surface roughness (Ra) and ion elution values were measured. The Kruskal-Wallis and Mann-Whitney U tests were used to analyze the ion elution data before and after thermocycling, and the effect of thermocycling on ion elution was assessed by the Wilcoxon signed rank test. Ra data were analyzed with 2-way analysis of variance (ANOVA) and the Tukey honestly significant difference tests (α=.05). Results: Elution of some ions varied depending on the material-firing pair before (Al, As, B, Ba, Cr, Cu, Li, Mg, Na, P, and Zn) and after (Al, As, B, Ba, Be, Ca, Cd, Co, Cr, Cu, K, Li, Mg, Na, P, Y, and Zn) thermocycling. Before thermocycling, all firing groups within each material showed a similar number of significantly higher eluted ions. After thermocycling, the number of significantly higher eluted ions decreased in all materials, except for EX. The effect of thermocycling on the ion elution of the 1F group of Z (Al, Be, Ca, Cd, Co, Cr, Cu, K, Li, P, Y, and Zn), S (As, Be, Cd, Co, Cr, K, P, and Y), EX (B, Cu, and P), and E (B and Ba); 2F group of Z (Al, Be, Ca, Co, Cr, Cu, K, Li, P, and Y), S (Be, Cd, Co, K, Li, and Y), EX (P), and E (P); 4F group of Z (Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, K, Li, P, and Y), S (Al, Be, Cd, Co, Cr, Li, Mg, and Y), EX (Be, Ca, Cd, Co, K, Y, and Zn), and E (Ca and P) was nonsignificant (P≥.051). The interaction between material and repeated firings (P<.001) had a significant effect on Ra. For 1F groups, E showed the highest Ra (P≤.003), while Z had higher Ra than S (P=.009). For 2F groups, Z had higher Ra than S (P=.01). The differences among 4F groups were nonsignificant (P≥.677). An increased number of repeated firings (2F and 4F) decreased the Ra of E (P<.001). Conclusions: The effect of repeated firings and thermocycling on the chemical stability of the tested CAD-CAM materials varied. No clear trend was observed on the elution of different ions within material-firing pairs before thermocycling. However, thermocycling increased the number of significantly higher eluted ions for EX. The effect of thermocycling on the ion elution of materials varied depending on ions. Repeated firings decreased the surface roughness of E.