The aim of the study to evaluate the fracture resistance of a computer-aided design/computer-aided manufacturing (CAD/CAM) and three indirect composite materials for three different mesio-occluso-distal (MOD) inlay cavity designs. A total of 120 mandibular third molar were divided into three groups: (G1) non-proximal box, (G2) 2-mm proximal box, and (G3) 4-mm proximal box. Each cavity design received four composite materials: Estenia, Epricord (Kuraray, Japan), Tescera (Bisco, USA), and Cerasmart CAD/CAM blocks (GC, USA). The specimens were subjected to a compressive load at a crosshead speed of 1 mm/min. The data was analyzed using the two-way analysis of variance and Bonferroni post hoc test (p<0.05). Estenia exhibited significantly higher fracture strength than Epricord and Cerasmart in G1. In G2 and G3, there was no significant difference among the four materials. Using a non-proximal box design for the cavity can improve the fracture resistance of the inlay restoration.