Purpose: To assess the impact of fatigue loading on the internal and marginal fit of CAD/CAM–fabricated endocrowns for restoring endodontically treated molars using different machinable blocks. Materials and Methods: A total of 72 mandibular first molars were prepared using a standardized method and were divided into four groups (n = 18), each restored with a different CAD/CAM material: group V = polymer-infiltrated ceramic (Vita Enamic); group K = partially stabilized tetragonal zirconia (Katana); group E = lithium disilicate ceramic (IPS e.max CAD; and group B = polyetheretherketone (BioHPP). Endocrowns were subjected to thermomechanical fatigue loading. Internal and marginal adaptation of the endocrowns were examined at 66 points using the sectioning technique and a stereomicroscope. Data were analyzed using one-way ANOVA and Tukey post hoc test (α = .05). Results: Statistical tests showed that adhesive cementation resulted in significantly increased marginal and internal gap values in all regions in all four tested groups (P < .001). After thermomechanical fatigue loading, all regions in groups B and K showed a statistically significant difference, while no significant differences were found in the regions in group V (P > .05). In group E, the marginal (F = 71.00) and pulpal (F = 28.065) regions showed statistically significant differences (P < .001). Conclusion: Polymer-infiltrated ceramics showed the lowest gap even after thermomechanical fatigue loading and may therefore provide enhanced clinical survival of the restored tooth, favoring the use of this material for fabricating endocrown restorations.