In this paper, we study the 3D Helmholtz equation in a step-index waveguide with unbounded perturbation, allowing the presence of guided waves. Our assumptions on the perturbed and source terms are too few. On the basis of the Green's function for the 3D homogeneous Helmholtz equation in a step-index waveguide without perturbation, we introduce a generalized (out-going) Sommerfeld-Rellich radiation condition, and then we prove the uniqueness and existence of solutions for the studied 3D Helmholtz equation satisfying our radiation condition.