We have developed a computational method for accurately predicting the conformation of side-chain atoms when building a protein structure from a known homologous structure. A library of rotamers is used to model the side-chains, allowing an average of five to six different conformations per residue. Local sites of adjacent side-chains are defined throughout the protein, and all combinations of side-chain rotamers are evaluated within each site using a molecular mechanics force field enhanced by the inclusion of a solvation term. At each site, the lowest energy combination of side-chains is identified and added onto the fixed protein backbone. A series of test cases using the refined X-ray structure of alpha-lytic protease has shown that: (1) the force field can correctly predict up to 90% of side-chain rotamers; (2) the assumption of side-chain rotamer geometry is usually a very good approximation; and (3) the complete combinatorial conformation search is able overcome local minima and identify the lowest energy rotamer set for the protein in the absence of a starting bias to the correct structure. Tests with several pairs of homologous proteins have shown that the algorithm is quite successful at predicting side-chain conformation even when the protein backbone used to generate side-chain positions deviates from the correct conformation. The root-mean-square (r.m.s.) deviation of predicted side-chain atoms rises from 1.31 A (average r.m.s.d. 0.73 A) in a test case with the correct backbone to only 2.68 A (1.95 A average r.m.s.d.) in a test case with < 35% homology. The high accuracy of this method suggests that it may be a useful automated tool for modeling protein structure.