Objective <p>This study investigated the fracture resistance and mode of failure of CAD/CAM milled versus 3D printed resin composite inlays under the influence of thermocycling.</p> Materials and methods <p>Brilliant Crios CAD/CAM milled and Crowntec 3D printed resin composite materials were used in this study. Twenty sound freshly extracted human mandibular third molars were selected for this study and randomly divided based on manufacturing technique into two groups: CAD/CAM milled, and 3D printed resin composite inlays. A universal testing machine was used to estimate the fracture resistance, and the mode of failure was investigated for fractured specimens. Inferential statistics for evaluating and comparing milling and 3D-printed manufacturing techniques were carried out via independent samples t tests at the 0.05 significance level.</p> Results <p>While the 3D printing group recorded numerically higher fracture resistance, no statistically significant difference was found (<i>p</i> &gt; 0.05). Evaluating the mode of failure of the CAD/CAM milling group specimens revealed that there was no significant difference between all the recorded failure modes (<i>P</i> &gt; 0.05). On the other hand, a significant difference was revealed between the different recorded modes of failure in the 3D printing group (<i>P</i> &lt; 0.05).</p> Conclusions <p>Both 3D-printed, and CAD/CAM milled resin inlays had comparable fracture resistance that exceeded the physiological masticatory force in molar region; however, most of the failure modes recorded for both materials were irreparable failures involving more than half of the tooth and extending below the CEJ.</p> Clinical significance <p>3D printed resin composite material is a promising option in fabrication of indirect restorations with lower cost and more time saving. Long term clinical studies are recommended to evaluate clinical performance of 3D printed resin composite materials.</p>