Most of the reported covalent organic frameworks (COFs) so far are prepared from highly symmetric building blocks, which to some extent limits the expansion of COF diversity and complexity. Low-symmetric building blocks can be designed through a desymmetrized vertex strategy, which might be used to construct new topological COFs. But reports of COFs constructed by asymmetric building blocks are thus far very rare. Here, a feasible strategy to design asymmetric building blocks for COF synthesis is introduced, by simply varying the positions of functional groups in the monomer. As a proof of concept, two isomeric hexaphenylbenzene-based "two-in-one" type monomers (1,2,4-HPB-NH 2 and 1,3,5-HPB-NH 2 ) are designed and synthesized. To the authors' surprise, self-polycondensation of the asymmetric 1,2,4-HPB-NH 2 (i.e., the isomer of common C 3 -symmetric 1,3,5-HPB-NH 2 ) also affords highly crystalline COF (1,2,4-HPB-COF) similar to the symmetric 1,3,5-HPB-NH 2 counterpart with identical topological structure. The triangular porous structures of both HPB-based COFs are well resolved by powder X-ray diffraction (PXRD), theoretical simulations, nitrogen sorption, and morphologies analysis. This work demonstrates the "two-in-one" type asymmetric building blocks can also produce highly crystalline frameworks and thus provides a new structural design strategy for reticular chemistry.