Objective To demonstrate the fatigue behavior of CAD/CAM resin composite molar crowns using a mouth-motion step-stress fatigue test. Monolithic leucite-reinforced glass-ceramic crowns were used as a reference. Methods Fully anatomically shaped monolithic resin composite molar crowns (Lava Ultimate, n = 24) and leucite reinforced glass-ceramic crowns (IPS Empress CAD, n = 24) were fabricated using CAD/CAM systems. Crowns were cemented on aged dentin-like resin composite tooth replicas (Filtek Z100) with resin-based cements (RelyX Ultimate for Lava Ultimate or Multilink Automix for IPS Empress). Three step-stress profiles (aggressive, moderate and mild) were employed for the accelerated sliding-contact mouth-motion fatigue test. Twenty one crowns from each group were randomly distributed among these three profiles (1:2:4). Failure was designated as chip-off or bulk fracture. Optical and electronic microscopes were used to examine the occlusal surface and subsurface damages, as well as the material microstructures. Results The resin composite crowns showed only minor occlusal damage during mouth-motion step-stress fatigue loading up to 1700 N. Cross-sectional views revealed contact-induced cone cracks in all specimens, and flexural radial cracks in 2 crowns. Both cone and radial cracks were relatively small compared to the crown thickness. Extending these cracks to the threshold for catastrophic failure would require much higher indentation loads or more loading cycles. In contrast, all of the glass-ceramic crowns fractured, starting at loads of approximately 450 N. Significance Monolithic CAD/CAM resin composite crowns endure, with only superficial damage, fatigue loads 3 – 4 times higher than those causing catastrophic failure in glass-ceramic CAD crowns.