The CH4-flue gas replacement that occurs in structure H (sH) hydrates was investigated, with a primary focus on thermodynamic phase behavior, structure identification, heat flow monitoring, and dissociation enthalpy, for its dual function of CH4 recovery and CO2 sequestration. The significant shift in the equilibrium line of the CH4 + neohexane (2,2-dimethylbutane, NH) hydrates replaced with CO2 (10%) + N2 (90%) and CO2 (20%) + N2 (80%) indicates that CH4 molecules in the sH hydrates were significantly exchanged with flue gas mixtures. Furthermore, 13C NMR spectroscopy revealed that replacement using flue gas occurs without a structural transition, and that CO2 molecules preferentially attack CH4 molecules occupied in the medium 435663 cages of sH hydrates. The extent of the CH4 + NH - flue gas replacement was approximately 74%. During CH4 - flue gas replacement in sH hydrates, there was no significant change in heat flow associated with the dissociation and subsequent reformation of gas hydrates. Dissociation enthalpies of gas hydrates before and after replacement, measured using a high-pressure micro-differential scanning calorimeter (HP μ-DSC), also supported isostructural replacement with the high extent of reaction. This study reports the first experimental evidence of isostructural CH4 - flue gas replacement occurring in sH hydrates, and thus, might contribute to extending the potential fields of CH4 exploitation using a flue gas replacement, into sH natural gas hydrate reservoirs.