Small organic conjugated systems displaying one-dimensional stacking motifs in the solid state that facilitate charge propagation are highly desirable. Noncovalent interactions, although weak, can synergistically provide those supramolecular architectures with large binding energies and associated thermal integrity. Amongst the plethora of intermolecular interactions contributing toward the overall lattice energy and stability of the charge-propagation supramolecular architectures, H-bonding interactions are well-known to play a pivotal role. Despite their critical contribution, the positions of hydrogen atoms in X-ray crystallographic data are parameterized, which can lead to significant changes in the computed intermolecular interactions. Herein, we report for the first time an analysis of the role that the optimization of the H atoms in X-ray structures has in the computed intermolecular interactions energies in diketopyrrolopyrroles (DPPs). A large dataset comprising 94 dimer pairs from 19 different DPP-based systems, including three pigment analogues, was employed. In total, more than 1400 H–X chemical bonds were considered and optimized using the M06-2X density functional at the 6-311G(d) level. Intermolecular interactions were computed for the H-optimized geometries and compared to those from nonoptimized counterparts. We report that in 35 out of the 94 dimer pairs investigated (37%), the computed intermolecular interactions were at least 2.5 kJ mol–1 larger on progression to the H-optimized geometries. In turn, lower computed values were yielded upon H-optimization computed for 8 out of the 94 dimer pairs (8%), with one case exhibiting a difference greater than 2.5 kJ mol–1. In line with the negligible changes to electron density and wavefunction overlap, the computed changes on the transfer integrals for the hole and electron were always lower than 1 kJ mol–1. The observed changes to computed intermolecular interactions can play a critical role in determining the thermal integrity of the supramolecular structures and charge propagation channels, and thus in the absence of neutron diffraction data, H atoms should be optimized prior to computation. We envisage that the results herein will be of interest to the extensive scientific community devoted to the understanding of intermolecular interactions in organic conjugated systems and the realization of superior charge-transfer-mediating materials, and given the plethora of intermolecular interactions investigated, the results are not solely limited to DPP-based architectures.