Hydrogen-bonded organic frameworks (HOFs) are an emerging class of porous materials that hold promise for the adsorptive separation of industrially relevant gas mixtures. However, developing HOFs with high thermal stability and resistance to water remains a daunting challenge. We report here a microporous HOF (HIAM-103) assembled from a hexacarboxylate linker (2,4,6-trimethylbenzene-1,3,5-triylisophthalic acid, H 6 TMBTI). The compound crystallizes in the trigonal crystal system, and its structure is a four-fold interpenetrated network. Upon thermal activation, the single crystals remain intact, allowing for precise determination of the activated structure. HIAM-103 exhibits remarkable thermal and hydrothermal stability. Its microporous channels demonstrate selective adsorption of C 2 H 6 over C 2 H 4 and Xe over Kr, and its separation capability toward mixed gases has been validated by column breakthrough experiments under dry and humid conditions. The preferential gas adsorption sites and separation mechanisms have been uncovered through DFT analysis, which suggests that the methyl group decorated 1D channels are the primary reason for the selective adsorption.