Three types of opioid receptors-mu, delta, and kappa-belong to the rhodopsin subfamily in the G protein-coupled receptor superfamily. With the recent characterization of the high-resolution X-ray crystal structure of bovine rhodopsin, considerable attention has been focused on molecular modeling of these transmembrane proteins. In this study, a homology model of the mu opioid receptor was constructed based on the X-ray crystal structure of bovine rhodopsin. A phospholipid bilayer was built around the receptor, and two water layers were placed on both surfaces of the lipid bilayer. Molecular-dynamics simulations were carried out by using CHARMM for the entire system, which consisted of 316 amino acid residues, 92 phospholipid molecules, 8327 water molecules, and 11 chloride counter ions-40 931 atoms altogether. The whole system was equilibrated for 250 ps followed by another 2 ns dynamic simulation. The opioid ligand naltrexone was docked into the optimized model, and the critical amino acid residues for binding were identified. The mu opioid receptor homology model optimized in a complete membrane-aqueous system should provide a good starting point for further characterization of the binding modes for opioid ligands. Furthermore, the method developed herein will be applicable to molecular model building to other opioid receptors as well as other GPCRs.