PURPOSE: To evaluate the wear of computer-aided design/computer-aided manufacturing (CAD-CAM) dental ceramic materials opposed by enamel as a function of increased chewing forces. MATERIALS AND METHODS: The enamel cusps of healthy human third molar teeth (n = 40) opposed by materials from CAD-CAM dental ceramic groups (n = 10), including Vita Enamic® (ENA), a polymer-infiltrated ceramic network (PICN); GC Cerasmart® (CERA), a resin nanoceramic; Celtra® Duo (DUO), a zirconia-reinforced lithium silicate (ZLS) ceramic; and IPS e.max ZirCAD (ZIR), a polycrystalline zirconia, were exposed to chewing simulation (1,200,000 cycles; 120 N load; 1 Hz frequency; 0.7 mm lateral and 2 mm vertical motion). The wear of both enamel cusps and materials was quantified using a 3D laser scanner, and the wear mechanisms were evaluated by scanning electron microscopy (SEM). The results were analysed using Welch ANOVA and Kruskal Wallis test (α = .05). RESULTS: ZIR showed lower volume loss (0.02 ± 0.01 mm3) than ENA, CERA and DUO (P = .001, P = .018 and P = .005, respectively). The wear of cusp/DUO [0.59 mm3 (0.50-1.63 mm3)] was higher than cusp/CERA[0.17 mm3 (0.04-0.41 mm3)] (P = .007). ZIR showed completely different wear mechanism in SEM. CONCLUSION Composite structured materials such as PICN and ZLS ceramic exhibit more abrasive effect on opposing enamel due to their loss against wear, compared to uniform structured zirconia. The resin nanoceramic causes the lowest enamel wear thanks to its flexible nano-ceramic microstructure. While zirconia appears to be an enamel-friendly material in wear volume loss, it can cause microstructural defects of enamel.