Two chlorine-substituted isomers, ITIC-2Cl-β and a-ITIC-2Cl, were synthesized for potential use as nonfullerene acceptors. The two molecules differ in the position of chlorine atoms, leading to symmetric (ITIC-2Cl-β) and asymmetric (a-ITIC-2Cl) molecular configuration. In single crystals, the two molecules exhibit a completely different arrangement and stacking as derived from X-ray diffraction analysis. Whereas ITIC-2Cl-β has a linear packing structure, a-ITIC-2Cl forms a 3D interpenetrating network structure with shorter π-π distances and better molecular planarity. Therefore, a high power conversion efficiency of >12% is obtained by a-ITIC-2Cl-based devices. It is ∼10% higher than that of ITIC-2Cl-β-based devices due to the chlorine substituent effect. Thus the fine-tuning of the Cl-substituted position seems to be a promising strategy to construct a 3D interpenetrating charge transportation network and achieve higher performance organic solar cells (OSCs).