To develop an automated design technique, the sensitivity characteristics with respect to the design variables should be calculated. For many practical applications, the flexibility effects must be taken into consideration in order to describe the dynamic behavior of multibody systems involving deformable bodies. The proposed design methodology includes the sensitivity analysis of rigid-flexible multibody systems based on the direct differentiation method. The dynamic problem is formulated in Cartesian coordinates. For two examples (slider crank and vehicle with flexible chassis), the authors compare sensitivities obtained by the analytical method with sensitivities obtained by the finite difference method. The accuracy and other features of the proposed method are discussed.