Objectives: This study investigates the biomechanical interactions among restorative materials, cuspal preparation designs, and cement thickness in a cusp-replacing adhesive premolar restoration. Methods: Twenty-seven, 3D finite element (FE) models designed in a typical MODL restoration with three restorative materials (CAD/CAM ceramic block, indirect resin composite and glass-ceramic), three cavity preparation designs (buccal cuspal reduction of 1.0 mm, 1.5 mm and 2.0 mm in cuspal height) and three cement thicknesses (50 μm, 100 μm and 150 μm) were constructed to perform the simulations. The ANOVA test was performed to determine the relative importance of the investigated factors and main effects for each of the three investigated factor levels (restorative material, preparation design and cement thickness) in terms of the principal stress values. Results: The results indicated that the stress value in the restorative material was influenced primarily by the restorative material itself (95.49%). Preparation design was found as the major factor (>80%) affecting the stress values in the remaining tooth and luting cement. Conclusions: Using a low modulus restorative material presented more favorable biomechanical performance and the cuspal height might be at least 1.5 mm to critically reduce the stress values when cuspal-coverage treatment is considered. The investigated cement thickness only slightly affected the mechanical behavior of the cuspal replacement restoration. © 2007 Elsevier Ltd. All rights reserved.