The systematic fragmentation method fragments a large molecular system into smaller pieces, in such a way as to greatly reduce the computational cost while retaining nearly the accuracy of the parent ab initio electronic structure method. In order to attain the desired (sub-kcal/mol) accuracy, one must properly account for the nonbonded interactions between the separated fragments. Since, for a large molecular species, there can be a great many fragments and therefore a great many nonbonded interactions, computations of the nonbonded interactions can be very time-consuming. The present work explores the efficacy of employing the effective fragment potential (EFP) method to obtain the nonbonded interactions since the EFP method has been shown previously to capture nonbonded interactions with an accuracy that is often comparable to that of second-order perturbation theory. It is demonstrated that for nonbonded interactions that are not high on the repulsive wall (generally >2.7 Å), the EFP method appears to be a viable approach for evaluating the nonbonded interactions. The efficacy of the EFP method for this purpose is illustrated by comparing the method to ab initio methods for small water clusters, the ZOVGAS molecule, retinal, and the α-helix. Using SFM with EFP for nonbonded interactions yields an error of 0.2 kcal/mol for the retinal cis−trans isomerization and a mean error of 1.0 kcal/mol for the isomerization energies of five small (120−170 atoms) α-helices.