The algorithm by Northrup, Allison, and McCammon [J. Chem. Phys. 80, 1517 (1984)] has been used for two decades for calculating the diffusion-influenced rate-constants of enzymatic reactions. Although many interesting results have been obtained, the algorithm is based on the assumption that substrate-substrate interactions can be neglected. This approximation may not be valid when the concentration of the ligand is high. In this work, we constructed a simulation model that can take substrate-substrate interactions into account. We first validated the model by carrying out simulations in ways that could be compared to analytical theories. We then carried out simulations to examine the possible effects of substrate-substrate interactions on diffusion-controlled reaction rates. For a substrate concentration of 0.1 mM, we found that the diffusion-controlled reaction rates were not sensitive to whether substrate-substrate interactions were included. On the other hand, we observed significant influence of substrate-substrate interactions on calculated reaction rates at a substrate concentation of 0.1M. Therefore, a simulation model that takes substrate-substrate interactions into account is essential for reliably predicting diffusion-controlled reaction rates at high substrate concentrations, and one such simulation model is presented here. (C) 2004 American Institute of Physics.