© 2021 The AuthorsStatement of problem: Which surface treatment provides optimal surface roughness, microhardness, and wear behavior for computer-aided design and computer-aided manufacturing (CAD-CAM) materials and their enamel antagonists is unclear. Purpose: The purpose of this in vitro study was to evaluate the effect of surface treatment on the surface roughness, microhardness, and 2-body wear of different CAD-CAM materials and their enamel antagonists. Material and methods: Monolithic zirconia, polymer-infiltrated ceramic network, lithium disilicate, leucite-reinforced ceramic, zirconia-reinforced lithium silicate, and feldspathic ceramic specimens were sliced into 2-mm-thick rectangular plates and divided into polished or glazed subgroups (n=6). After surface roughness and microhardness measurements, the specimens were loaded at 49 N for 250 000 cycles and simultaneously thermocycled (5 °C and 55 °C). All specimens were scanned before and after the wear test by using a scanner. The volumetric loss and wear depth of the materials and the volumetric and height loss of the enamel were calculated, and scanning electron microscope images of the specimens were made. Multiple 2-way ANOVAs and Tukey honestly significant difference tests were used to assess the effect of material and surface treatment on surface roughness, microhardness, and wear behavior of materials and enamel (α=.05). Results: Material and surface treatment interactions affected the surface roughness (P<.001), microhardness (P<.001), volumetric loss of materials (P=.044), and height loss of enamel (P<.001). Conclusions: Polishing resulted in higher surface roughness and microhardness than glazing. Volumetric loss depended on the material, which affected the height loss of the antagonists. Glazing and polishing had similar effects on the volumetric loss of materials and antagonists. No correlation was found between the wear of materials and the antagonists, nor between the surface roughness of materials and the volumetric loss of materials or antagonists.