RegioSQM is a new computational method that identifies the aromatic carbon with highest proton affinity (Figure ) using the PM3 semiempirical method. It has been applied to a set of more than 525 EAS reactions compiled from the literature. With an energy cutoff of 1.0 kcal/mol to define sites with indistinguishable proton affinities (Figure ), RegioSQM correctly predicts the mono-halogenation of 396 of these reactions and the bis-functionalization of an additional 39 compounds, leading to an overall success rate of 81%. The number of correct predictions increases 92% and 96% when considering examples with multiple predicted reactive sites as correct if the experimental site is among those identified by RegioSQM at energy cutoffs at 1 and 3.0 kcal/mol, respectively. This increase in correct predictions comes at the expense of more incorrect predictions. RegioSQM fails to identify the experimental site of reaction in 13 cases (<3%).