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Objectives The purpose of this in vitro study was to evaluate the influence of thermodynamic loading on the durability and fracture resistance behavior of occlusal veneers fabricated from different biomedical dental CAD/CAM materials. Methods The occlusal surfaces of 64 extracted premolars were prepared in the enamel layer and restored with occlusal veneers with a fissure/cusp thickness of 0.5/0.8 mm made from four different dental CAD/CAM materials: group LD lithium disilicate (e.max CAD), group LS zirconia-reinforced lithium silicate (Vita Suprinity), group PI polymer-infiltrated ceramic (Vita Enamic), and group PM polymethylmethacrylate PMMA (Telio CAD). The prepared teeth were etched with phosphoric acid. The occlusal veneers were then bonded using an adhesive luting system (Multilink Primer A/B and Multilink Automix luting resin). Half of the specimens were subjected to thermodynamic loading in a chewing simulator (1.2 million cycles at 98 N). All specimens were quasi-statically loaded until fracture. The statistical analysis was made using the t -test and one-way ANOVA followed by the Tukey HSD test (α = 0.05). Results All aged specimens survived the thermodynamic loading. Thermodynamic loading significantly raised the fracture resistance in groups LS, PI, and PM (P < 0.03). Occlusal veneers made from lithium disilicate and zirconia-reinforced lithium silicate recorded higher fracture resistance than those made from polymer-infiltrated ceramic and PMMA resin. Conclusions All tested dental CAD/CAM biomaterials exhibited a fracture resistance considerably exceeding the average occlusal force in the posterior dentition. Therefore, they might present a viable long-term treatment for restoring the occlusal surfaces of posterior teeth. [ABSTRACT FROM AUTHOR]