This study determined the relative contribution of changes (investigated design factors) in prosthesis retainer design (thickness, height and angle) and load condition on the biomechanical response of a posterior resin-bonded fixed partial denture (RBFPD) using finite element (FE) analysis and quality engineering (Taguchi) method. After FE model validation, nine FE models corresponding to a Taguchi L9 array were constructed to perform numerical simulations to simulate RBFPD mechanical responses. The Taguchi method was employed to determine the significance of each investigated factor in controlling stress. The results indicated that the load condition was the major factor affecting the stress values (79% in tooth and 98% in prosthesis). Retainer height was found to be the main prosthesis design factor affecting the stress values (12% in tooth and 1% in prosthesis), followed by retainer thickness (8% in tooth and 1% in prosthesis). Retainer extended angle was found to have no significant effect on the tooth and prosthesis stress values. Increased stress values were found with lateral force, greater retainer height dimension and by increasing the retainer thickness. The combined use of FE analysis and the Taguchi method efficiently identified the relative contributions of multiple RBFPD factors and indicated that retainer height was the most critical retainer dimension factor in attaining proper occlusal adjustment. Reduced lateral occlusal force application is recommended to obtain a better force-transmission mechanism.