This study is concerned with clathrate hydrate formation from natural gas for its storage and/or transport. During each hydrate-forming operation using an isobaric reactor into which a feed gas (i.e., natural gas with a fixed composition) is continuously supplied, the composition of the gas phase inside the reactor should continuously change as the result of preferential uptake of some species from the gas phase into the hydrate, which should, in turn, affect the subsequent hydrate formation. In a previous paper (Tsuji, H.; Kobayashi, T.; Okano, Y.; Ohmura, R.; Yasuoka, K.; Mori, Y. H. Energy Fuels 2005, 19, 1587-1597), we reported a computational scheme of thermodynamic simulations of such operations and its application to the hydrate formation from a methane + ethane + propane mixture. In the present study, we have extended the scheme to be applicable to a gas mixture composed of an arbitrary number of species and have applied it to methane-based gas mixtures simulating natural gas that may contain traces of hydrocarbons heavier than propane. Our major concern is the effects of such trace components in the feed gas during each long-term hydrate-forming operation. The vapor of some heavy hydrocarbons may accumulate in the gas phase inside the reactor, possibly leading to either the onset of its condensation or a structural transition of the hydrate being formed inside the reactor, which may pose a problem regarding the quality control of the hydrate products. The possibility of the occurrence of such a phase change or hydrate-structural transition is discussed on the basis of thermodynamic simulations.