Developing propane-selective adsorbents for propane/propene (C3H8/C3H6) separation can energy-efficiently produce high-purity C3H6, but it remains unexploited in porous hydrogen-bonded organic frameworks (HOFs) because of lacking effective C3H8 binding sites. Reticular chemistry provides a powerful strategy for fine-tuning of pore size and functionality; however, this strategy is extremely challenging to be implemented in HOFs owing to the weak H-bonds with poor directionality. Herein, we report, for the first time, the implementation of a reticular chemistry strategy to design and synthesize a series of isoreticular HOFs (ZJU-HOF-59-ZJU-HOF-62) for achieving highly efficient C3H8/C3H6 separation. Four isoreticular HOFs were constructed by four tetracarboxylic ligands, in which their pore sizes and functional sites are systematically engineered. These HOFs exhibit a tunable and gradually improved binding preference of C3H8 over C3H6. Among them, ZJU-HOF-62 with abundant dialkynyl sites and suitable pore sizes demonstrates the fully inverse C3H8/C3H6 separation, exhibiting the highest C3H8 uptake (146.8 cm3 g-1) and C3H8/C3H6 selectivity (1.53) at 298 K and 1 bar. Theoretical calculations reveal that multiple dialkynyl and carboxylic sites provide stronger multipoint H-bonding and van der Waals interactions with C3H8 than C3H6. The excellent separation capacity of ZJU-HOF-62 for actual C3H8/C3H6 mixtures was proved by dynamic breakthrough experiments, providing a maximum C3H6 productivity of 12.1 L kg-1. This work opens the design of porous HOFs for challenging C3H8/C3H6 separation.