SUMMARY Objectives: To evaluate the effect of endodontic access on the failure load resistance of both adhesively and conventionally luted, full-contour monolithic yttria-stabilized zirconium dioxide (Y-TZP) and adhesively luted lithium disilicate (LD) crowns cemented on prepared teeth. Methods and Materials: Seventy-two human maxillary molars were prepared per respective guidelines for all-ceramic crowns with one group (n=24) restored with LD and the other (n=48) receiving Y-TZP crowns. Preparations were scanned using computer-aided design/computer-aided milling (CAD/CAM) technology, and milled crowns were sintered following manufacturer recommendations. All LD crowns and half (n=24) of the Y-TZP crowns were adhesively cemented, while the remaining Y-TZP specimens were luted using a conventional glass ionomer cement (GIC). One LD group, one Y-TZP adhesive group, and one GIC-luted group (all n=12) then received endodontic access preparations by a board-certified endodontist: the pulp chambers were restored with a dual-cure, two-step, self-etch adhesive and a dual-cure resin composite core material. The access preparations were restored using a nano-hybrid resin composite after appropriate ceramic margin surface preparation. After 24 hours, all specimens were loaded axially until failure; mean failure loads were analyzed using Mann-Whitney U test (α=0.05) Results: Endodontic access did not significantly reduce the failure load of adhesively luted LD or Y-TZP crowns, but Y-TZP crowns with GIC cementation demonstrated significantly less failure load. Conclusions: These initial findings suggest that endodontic access preparation may not significantly affect failure load resistance of adhesively luted Y-TZP and LD crowns. Definitive recommendations cannot be proposed until fatigue testing and coronal seal evaluations have been accomplished.