Purpose: This study compared the fatigue life of human maxillary premolars restored with direct composites and indirect ceramic inlays in mesio-occlusodistal (MOD) cavities. Materials and Methods: Ten human maxillary premolars were divided into two groups of five and restored with (1) direct composite restorations, or (2) pressed ceramic restorations. Standardized MOD cavities were prepared for both groups. Teeth in the direct composite group were restored with Z250 composite and Single Bond adhesive, and those in the ceramic group were restored with IPS Empress ceramic inlays. The ceramic inlays were luted with Single Bond and RelyX ARC cement. Under the applied test load of 11.17 kg, strain measurements were recorded from an electric resistance stain gauge bonded to the buccal surface. These strains were recorded for the (1) intact tooth, (2) cavity preparation, and (3) restored tooth. These strain measurements were used to calculate the relative tooth compliance values for each tooth. The fatigue loading was applied until reinforcement loss was registered by the strain gauge. Results: A one-way ANOVA showed no significant compliance difference between the intact and restored tooth conditions, and no significant difference in fatigue cycles to failure between the two groups. Conclusion: There were both adhesive and cohesive failures in both restoration groups, indicating that the adhesive joint is not the only weak link in these restorations.