Indiana University-Purdue University Indianapolis (IUPUI) / Background: New glass ceramics and Computer-Aided Design/Computer Assisted Manufacture (CAD/CAM) have become common aspects of modern dentistry. The use of posterior ceramic crowns with a high level of esthetics, fabricated using the CAD/CAM technology is a current treatment modality. Several materials have been used to fabricate these crowns, including lithium disilicate glass-ceramics, which have not been fully investigated in the literature. Objective: to investigate the load to fracture of lithium disilicate glass ceramic posterior crowns fabricated by CAD/CAM technology with different material thicknesses adhesively cemented on epoxy resin. Methods: Four groups of different ceramic thicknesses (0.5 mm, 1 mm, 1.5 mm, and 2 mm) were fabricated by milling CAD/CAM lithium disilicate IPS emax CAD blocks. A total of 68 posterior crowns were surface treated and luted with a resin adhesive cement on an epoxy resin model. Samples were fatigued then loaded to fracture using a universal testing machine to test the fracture strength. Statistical comparisons between various crown thicknesses were performed using one-way ANOVA followed by Fisher's Protected Least Significant Differences. Results: There was a significant difference in the load-to-fracture (N) value for all comparisons of the four thickness groups (p < 0.0001), except 2 mm vs. 1.5 mm (p = 0.325). The mean load-to-fracture (N) was significantly higher for 2 mm than for 1 mm or 0.5 mm. Additionally, the mean load-to-fracture was significantly higher for 1.5 mm than for 1 mm or 0.5 mm. Furthermore, the mean load-to-fracture was significantly higher for 1 mm than for 0.5 mm. Conclusion: Within the limitation of this study, it is advisable for clinical applications to consider a crown thickness of 1.5 mm or greater of milled lithium disilicate for posterior single teeth.