Depletion perturbation theory was developed within the framework of an advanced hexagonal nodal diffusion method. A similarity transformation method was used to compute the mathematical generalized adjointsfrom the corresponding physical system because it was more convenient to utilize the numerical algorithms and codes developed for solving the real system equations. The methods were implemented using the DIF3D code for the flux solutions and were applied to a sample problem using a hexagonal geometry lattice. In all cases, there was good agreement between the results of direct subtraction and the depletion sensitivities. This work indicates it is feasible to generate depletion sensitivities within the framework of advanced nodal diffusion methods.