A numerical model is presented for the estimation of Wave Energy Converter (WEC) performance in variable bathymetry regions, taking into account the interaction of the floating units with the bottom topography. The proposed method is based on a coupled-mode model for the propagation of the water waves over the general bottom topography, in combination with a Boundary Element Method for the treatment of the diffraction/radiation problems and the evaluation of the flow details on the local scale of the energy absorbers. An important feature of the present method is that it is free of mild bottom slope assumptions and restrictions and it is able to resolve the 3D wave field all over the water column, in variable bathymetry regions including the interactions of floating bodies of general shape. Numerical results are presented concerning the wave field and the power output of a single device in inhomogeneous environment, focusing on the effect of the shape of the floater. Extensions of the method to treat the WEC arrays in variable bathymetry regions are also presented and discussed.