The effect of a solvent on the activity coefficient of a macromolecule in crowding media was investigated using the hard-sphere model. The crowding media comprised solvent molecules and crowding agents, and the activity coefficient of a macromolecule immersed in the media was calculated using the integral equation theory. The dependence of the activity coefficient on the concentration of crowding agent for the explicit-solvent model was completely different from that for the inert-solvent model, which has been adopted in conventional studies of crowding problems. Those results indicate that solvent granularity can play an important role in the description of the activity coefficient of macromolecules. (C) 2009 Elsevier B. V. All rights reserved.