This paper reports on the process-fatigue relation of lithium disilicate glass ceramic (LDGC) using low-cycle, high-load Hertzian indentations with a rigid indenter to simulate teeth grinding/clenching of LDGC restorations with different surface asperities obtained in CAD/CAM milling, sintering, polishing and glazing. The maximum contact stresses were evaluated as functions of the number of load cycles and surface treatments using the Hertzian model. Indentation-induced surface damage was viewed using scanning electron microscopy (SEM) to understand the relationships among microstructures, surface asperities, crack morphology and propagation. Different processes and surface treatments significantly affected the maximum contact stresses of indented LDGC surfaces (ANOVA, p < 0.05), which were all significantly reduced with the number of cycles (ANOVA, p < 0.05). Quasi-plastic deformation was dominant in single-cycle indentation of all processed and treated surfaces. In higher cycle indentations, inner cone cracks were formed on all surfaces; median and transverse cracks were formed on the roughest surfaces processed by CAD/CAM milling and sintering. Ring cracks, fretting, pulverization, micro-bridges, surface smearing and wedging, and edge chippings were also propagated on all surfaces. The process-fatigue relation provides an understanding of the mechanical functions of surface asperities produced in different processes and treatments. It indicates that the mechanically assisted growth of surface asperities with different roughness strongly affected the indentation-induced surface damage. Finally, the smoothest surfaces produced by CAD/CAM milling, polishing and sintering sustained the highest contact stresses and the least fatigue damage at higher cycles, ensuring their superior fatigue performance compared to other processed LDGC surfaces.Copyright © 2020 Elsevier Ltd. All rights reserved.