Currently, there is no consensus on whether crowns fabricated via computer-aided design/computer-aided manufacturing (CAD/CAM) need to be replaced following an endodontic procedure. The aim of this in vitro study was to evaluate the effect of endodontic access preparation and repair on the failure load of lithium disilicate and resin nanoceramic crowns. The hypothesis was that there would be no difference in the failure load between the intact and repaired crowns. Eighty identical mandibular CAD/CAM crowns (40 lithium disilicate glass ceramic [IPS e.max CAD] and 40 resin nanoceramic [Lava Ultimate]) were milled and cemented on 80 identical polymethyl methacrylate resin dies. A standardized endodontic access preparation was made in half the specimens and restored with composite resin. All crowns were subjected to an occlusal load with a hydraulic testing machine until failure. Based on the Wilcoxon rank sum test, the load to failure was significantly higher for the lithium disilicate crowns than for resin nanoceramic crowns in both the intact and repaired groups (P < 0.001). For the lithium disilicate crowns, the failure load was significantly higher for intact than for repaired specimens (P = 0.002). However, there was no significant difference between intact and repaired specimens for resin nanoceramic. The repair of lithium disilicate and resin nanoceramic CAD/CAM crowns may provide a serviceable restoration under normal occlusal loads. However, replacement would be prudent in cases where parafunctional occlusal loading is suspected, the crown was not adhesively cemented, or there is an obvious defect in the existing crown.