Orbital interactions in electrophilic aromatic substitution reactions of anisol, nitrobenzene, and some other analogues were studied. A single frontier orbital (FO), i.e., the HOMO of substituted benzenes, particularly of nitrobenzene, does not account for the regioselectivities of the reaction. We first applied configuration analysis to identify the relative importance of orbital interactions between an electrophile (H+ in this work) and the substituted benzenes. We herein define the reactive hybrid orbital (RHO) method for measuring the reactivity of each carbon atom of substituted benzene. An RHO is made by combining all occupied molecular orbitals properly so that the reactivity index for a reaction center, which is similar to superdelocalizability, is maximized. The RHO reactivity indices, lambda(oc), rho(oc), and rho'(oc), were shown to predict correctly the experimentally observed regioselectivity and reactivity in the electrophilic aromatic substitution reactions of anisol, nitrobenzene, and other monosubstituted benzenes. Moreover, it was shown that the RHO values for carbon atoms in a polycyclic aromatic hydrocarbon are in good agreement with experimentally determined partial rate factors.