Objective To investigate fatigue fracture resistance and wear behavior of a polymer infiltrated ceramic network (PICN) material (ENAMIC, Vita Zahnfabrik). Methods Anatomically shaped ENAMIC monolithic crowns were milled using a CAD/CAM system. The crowns were cemented on aged dentin-like composite abutments (Z100, 3M ESPE) with resin-based cement (Vita DUO Cement, Vita). The specimens were subjected to 2 types of fatigue and wear tests: (1) accelerated sliding-contact mouth-motion step-stress fatigue test (n = 24) in water; and (2) long-term sliding-contact mouth-motion fatigue/wear test using a clinically relevant load (P = 200 N, n = 8) in water. Failure was designated as chip-off or bulk fracture. Optical and scanning electron microscopes were used to examine the occlusal surface and subsurface damage, as well as to reveal the material’s microstructure. In addition, wear volume and depth were measured by x-ray micro-computed tomography. Results For accelerated mouth-motion step-stress fatigue testing, 3 out of the 24 ENAMIC crowns fractured following cyclic loading up to 1700 N. Minor occlusal damage and contact-induced cone cracks were observed in all surviving specimens, but no flexural radial cracks were seen. For long-term mouth-motion fatigue/wear testing under a 200 N load in water, a small wear scar without significant cracks was observed in all 8 tested ENAMIC crowns. Significance Monolithic CAD/CAM ENAMIC crowns showed superior resistance to sliding-contact fatigue fracture and wear.