The present paper presents an integrated computer-aided engineering (CAE) approach combining digital imaging, solid modeling, robust design methodology, and finite element analysis in order to conduct a parametric investigation of the design of locked plating systems. The present study allows for understanding the contributions of different design parameters on the biomechanics and reliability of these systems. Furthermore, the present approach will lead to exploration of optimum design parameters that will result in robust system performance. Three-dimensional surface models of cortical and cancellous femoral bone were derived via digital computed tomography (CT) image processing techniques and a medical imaging analysis program. A nine orthogonal array matrix simulation (L9) was conducted using finite element methods to study the effects of the various design parameters on plate performance. The introduced technique was demonstrated and experimentally verified on a case study using a Smith & Nephew PERI- LOC distal femur locking plate and a Synthes Less Invasive Stabilization System (LISS).