Analyzing acoustic-structural systems such as automobiles and aircraft, the FRF-based substructuring (FBS) method is one of the most powerful tools. In this paper, a general procedure for the parametric sensitivity analysis of vibro-acoustic problems has been presented using the multi-domain FRF-based substructuring formulation. For an acoustic-structural system sub-structured by multiple domains, the substructuring formulation gives the reaction farces on the interface boundaries. The design sensitivity formula is obtained from the direct differentiation of the reaction force expression with respect to the design vector. As a practical application, the proposed design sensitivity formula is applied to an engine mount system of passenger car. An objective of the problem is to identify the most effective engine mounts and bushes in minimizing the interior noise over the concerned rpm range. The comparison of the sensitivity results with those of the finite difference method shows excellent agreement. In addition, stiffness modifications of the mounts and bushes identified through the design sensitivity analysis lead to a successful decrease of the interior noise. This results show usefulness of the present method very well.