A theoretical scheme to evaluate effective, screened interactions between fragments is proposed within the framework of the fragment molecular orbital (FMO) method. In this theory, the presence of implicit, dielectric continuum solvent is not assumed, but only the information on bare, inter-fragment interaction energies obtained through the FMO calculation for explicit, molecular system is employed. The effective interactions with inclusion of entropic effect are then described and optimized as a consequence of inter-fragment correlations on the basis of classical-mechanical many-body theories. Test calculations for a simple model system and a realistic protein system are performed, and their implications are discussed. (C) 2012 Elsevier B.V. All rights reserved.