Studies of the thermodynamic stability of clathrate hydrates of natural gas (mostly methane) is important in fields such as offshore gas exploitation and energy storage. Two approaches were used to study the effect of unlike dispersion interactions on methane clathrate hydrates: grand canonical Monte Carlo simulations (which yield adsorption data directly and can be used to infer phase equilibria), and estimation of the heat of dissociation coupled with the Clausius–Clapeyron equation (to calculate the phase equilibria, at the expense of providing no information about the adsorption behavior). It was found that the adsorption isotherm parameters change monotonically with respect to unlike dispersion interactions, although a perfect fit to experimentally-derived values may not be possible, at least using the force fields considered in this study. The heat of dissociation changes monotonically due to changes in the unlike dispersion interaction, and a best fit value of the Berthelot correction factor is achieved.