In this work, we present a quantum mechanical approach for the simulation of Si/SiO2 interface roughness scattering in silicon nanowire transistors (SNWTs). The simulation domain is discretized with a three-dimensional (3D) finite element mesh, and the microscopic structure of the Si/SiO2 interface roughness is directly implemented. The 3D Schrödinger equation with open boundary conditions is solved by the non-equilibrium Green’s function method together with the coupled mode space approach. The 3D electrostatics in the device is rigorously treated by solving a 3D Poisson equation with the finite element method. Although we mainly focus on computational techniques in this paper, the physics of SRS in SNWTs and its impact on the device characteristics are also briefly discussed.