This study compares the results of the general effective fragment potential (EFP2) method to the results of a previous combined coupled cluster with single, double, and perturbative triple excitations [CCSD(T)] and symmetry-adapted perturbation theory (SAPT) study [Sinnokrot and Sherrill, J. Am. Chem. Soc., 2004, 126, 7690] on substituent effects in π−π interactions. EFP2 is found to accurately model the binding energies of the benzene−benzene, benzene−phenol, benzene−toluene, benzene−fluorobenzene, and benzene−benzonitrile dimers, as compared with high-level methods [Sinnokrot and Sherrill, J. Am. Chem. Soc., 2004, 126, 7690], but at a fraction of the computational cost of CCSD(T). In addition, an EFP-based Monte Carlo/simulated annealing study was undertaken to examine the potential energy surface of the substituted dimers.