Adsorptive separation of alkane isomers, especially the efficient separation of mono- and dibranched alkanes, remains challenging in the petrochemical industry. We report here the discrimination of alkane isomers through a thermodynamically driven mechanism by a highly stable calcium-based metal-organic framework. This newly developed 3D structure is built on a tetracarboxylate linker, featuring 1D channels with optimal pore dimensions to discriminate alkane isomers.