We have utilized two different computational techniques, free energy perturbation and finite difference Poisson-Boltzmann calculations, to estimate relative free energies of hydration for a series of organophosphorus molecules. The two methods are shown to give comparable results for small molecules with the general structure CH3PO2-X-CH3 (where X = O, NH, or CH2). For larger organophosphorus molecules, free energy perturbation techniques failed to give consistent results, but the Poisson-Boltzmann-method gave results that agreed qualitatively with those obtained for the smaller molecules and with experimental measurements of hydration energies for similar compounds. We believe that this is one of the first studies to utilize Poisson-Boltzmann calculations to estimate relative hydration energies for a series of analogous molecules. These studies also further highlight the potential difficulties that are sometimes encountered when molecular dynamics-based free energy perturbation techniques are used to study molecules with considerable conformational flexibility.