Purpose: To assess wear, fatigue, and fracture resistance of different CAD/CAM onlays, milled from monolithic Zirconia (Zr), hybrid ceramic (EN), and lithium disilicate (LS), when used as abutments for removable partial denture frameworks fabricated from acetal resin (AR) or cobalt-chromium (Co-Cr). Methods: Standard onlays and RPD framework were designed and milled using CAD/CAM. Onlays were cemented with resin cement to identical teeth models. The RPD’s occlusal rest surface and the ceramic onlays’ rest seats were both 3D scanned before and after 750,000 mechanical load cycles (50 N) and 8,000 thermal cycles (5-55°C) in a chewing simulator. The volumetric loss was measured using 3D image processing software, and the failure of the samples was detected using a stereomicroscope. The fracture resistance was tested by loading to failure in a universal testing machine. The fatigue failure results were analyzed with Fisher's exact probability test and the wear and fracture resistance data were analyzed using two-way ANOVA and Bonferroni Post-hoc test (P<0.05). Results: A significant difference (p<0.05) was found between the tested experimental groups in wear, fatigue, and fracture resistance. Zr/Co-Cr combinations exhibited the least wear and the highest fatigue and fracture resistance (P<0.05), while the highest wear and least fatigue and fracture resistance were recorded for EN/AR group (p<0.05). Conclusions: Zr onlays demonstrated a conservative treatment option with superior mechanical behavior when used as an onlay abutment, regardless of the RPD framework material used. The AR framework is not recommended in the posterior region for removable partial dentures.