Little is known about the fracture strength, retention, and adaptation of post-and-cores fabricated with novel tooth-colored materials by computer-aided design and computer-aided manufacturing (CAD-CAM).The purpose of this in vitro study was to investigate the fracture strength, pull-out bond strength (POBS), and volume of luting agent of endodontically treated premolars restored with post-and-cores milled from different CAD-CAM materials.Post spaces were prepared in 80 human premolars in which post-and-cores fabricated with polyetheretherketone (PK; Ceramill PEEK), nanohybrid composite resin (BB; Brava Block), polymer-infiltrated ceramic (EN; VITA Enamic), and fiber-reinforced epoxy resin (GF; Fiber Cad PostCore) CAD-CAM materials were luted (n=20). All specimens were subjected to thermal aging (3000 cycles at 5 °C and 55 °C with a 20-second dwell time). Half of the specimens were subjected to mechanical fatigue (250 000 cycles at 5 Hz) before fracture strength testing, while the other half was submitted to POBS testing and volume of luting agent measurement. Fracture strength data were analyzed by 1-way ANOVA, while POBS and volume of luting agent data were submitted to Kruskal-Wallis followed by the Bonferroni-Dunn multiple comparison tests. The correlation between POBS and the volume of luting agent was determined by the Spearman test (α=.05).POBS of GF was significantly higher than that for PK (P.001); however, failure load (P=.160) and volume of luting agent (P=.390) values did not differ. EN showed the highest percentage of catastrophic failures (20%), while PK exhibited only core deformations. POBS and cement film volume were not significantly correlated (P.05).Different CAD-CAM materials did not influence the fracture strength and volume of luting agent of post-and-cores. Post-and-cores made with PEEK blocks showed lower bond strength to intracanal dentin than those made with fiber-reinforced epoxy resin blocks. No significant correlation was found between bond strength and the volume of luting agent.