In a crown system, core fracture requires replacement of the restoration. Understanding maximum principal stress concentration in the veneered core of a tooth-crown system as a function of variations in clinically relevant parameters is crucial in the rational design of crown systems. This study evaluated the main and interacting effects of a set of clinical variables on the maximum principal stress (MPS) in the core of an anatomically correct veneer-core-cement-tooth model. A 3D CAD model of a mandibular first molar crown was generated; tooth preparation was modeled by reducing the proximal walls by 1.5 mm and the occlusal surface by 2.0 mm. A cemented veneered core crown was modeled on the preparation. This “crown system” permitted finite element model investigation of the main and interacting effects of proximal wall height reduction, core material, core thickness, cement modulus, cement thickness, and load position on the maximum stress distribution in a factorial design. Analysis of variance was used to identify the main and interacting influences on the level of MPS in the crown core. Statistical significance was set at . MPS levels varied as a function of two-way interactions between the following: core thickness and load position; cement thickness and load position; cement modulus and load position; cement thickness and core thickness; and cement thickness and cement modulus; and also three-way interactions among the load position, core material, and proximal wall height reduction, and among the core thickness, cement thickness, and cement modulus. MPS in the crown-tooth system is influenced by the design parameters and also by the interaction among them. Hence, while the geometry of molar crowns is complex, these analyses identify the factors that influence MPS and suggest levels that will minimize the core MPS in future studies of crown design.