Halogens are present in a significant number of drugs, contributing favorably to ligand-protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand-protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C-X···HBD orientations. Notably, the orientation dependence of the halogen-HBD (X-HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from -2 to -14 kcal/mol. This contrasts halogen bonds in that X-HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand-protein binding and, therefore, should be actively considered during rational ligand design.