Based on the random vibration theory, a response spectrum method is developed for seismic response analysis of linear, multi-degree-of-freedom structures under multi-support excitations is developed. Various response quantities, including the mean and variance of the peak response, the response mean frequency, are obtained from proposed combination rules in terms of the mean response spectrum. This method makes it possible to apply the response spectrum to the seismic reliability analysis of structures subjected to multi-support excitations. Considering that the tedious numerical integration is required to compute the spectral parameters and correlation coefficients in above combination rules, this paper further offers simplified procedures for their computation, which enhance dramatically the computational efficiency of the suggested method. The proposed procedure is demonstrated for tow numerical examples: (1) two-span continuous beam; (2) two-tower cabled-stayed bridge by using Monte Carlo simulation (MC). For this purpose, this paper also presents an approach to simulation of ground motions, which can take into account both mean and variation properties of response spectrum. Computed results based on the response spectrum method are in good agreement with Monte Carlo simulation results. And compared with the MSRS method, a well-developed multi-support response spectrum method, the proposed method has an incomparable computational efficiency.