To evaluate the marginal adaptation of endodontically treated molars restored with CAD/CAM composite resin endocrowns either with or without reinforcement by fibre reinforced composites (FRCs), used in different configurations. 32 human endodontically treated molars were cut 2 mm over the CEJ. Two interproximal boxes were created with the margins located 1 mm below the CEJ (distal box) and 1 mm over the CEJ (mesial box). All specimens were divided in four groups (n = 8). The pulp chamber was filled with: group 1 (control), hybrid resin composite (G-aenial Posterior, GC); group 2, as group 1 but covered by 3 meshes of E-glass fibres (EverStick NET, Stick Tech); group 3, FRC resin (EverX Posterior, GC); group 4, as group 3 but covered by 3 meshes of E-glass fibres. The crowns of all teeth were restored with CAD/CAM composite resin endocrowns (LAVA Ultimate, 3M). All specimens were thermo-mechanically loaded in a computer-controlled chewing machine (600,000 cycles, 1.6 Hz, 49 N and simultaneously 1500 thermo-cycles, 60 s, 5-55 °C). Marginal analysis before and after the loading was carried out on epoxy replicas by SEM at 200× magnification. For all the groups, the percentage values of perfect marginal adaptation after loading were always significantly lower than before loading (p < 0.05). The marginal adaptation before and after loading was not significantly different between the experimental groups (p > 0.05). Within the limitations of this in vitro study, the use of FRCs to reinforce the pulp chamber of devitalized molars restored with CAD/CAM composite resin restorations did not significantly influenced their marginal quality.