Activating and deactivating abilities of several substituents (-CH3, -F, -NH2, -NO2) in indole have been theoretically studied using a series of electron density based reactivity indices. Calculations have been performed at the B3LYP/6-311++G(2d,2p) level. An energetic criterion based on the proton affinities (PAs) has been employed to check the validity of these reactivity indices. Relative PAs reflect the ortho and para orientation ability of -CH3, -F, and -NH2 groups, whereas the large deactivating effect of -NO2 is mainly observed at these positions. Also, substitutions in carbons 2 and 6 (IUPAC nomenclature) activate/deactivate carbons 6 and 2, respectively. Inductive effects are also reflected on the values of the relative PAs. The -CH3 group is shown to have inductive electron-withdrawing character instead of electron-releasing with its activating ability being due to a small mesomeric electron-releasing character. pi atomic electron populations and the zz component of the atomic quadrupole electric tensor qualitatively explain the order of PAs. Fukui indices approximately predict the results obtained by the previous properties, whereas no correlation is found between the values of the (2)rho(r) at the secondary charge concentrations and the PA scale.