Montmorillonite (Mt) has high cation exchange capacity and thus has been studied extensively for its cation exchange interactions with other cations. However, molecular simulations for the forces governing the cation exchange on Mt surfaces or in the interlayer spaces were limited. In this study, Mt with K+ and Na+ in the interlayer spaces was tested for its cation exchange with Cd2+ in solution and the forces driving the cation exchange reaction were simulated by molecular simulations. The experimental results showed that Na+ in Na + Mt was completely exchanged by Cd2+, while only 50% of K+ in K + Mt was exchanged by Cd2+. A larger d-value was noticed for Na + Mt in comparison to K + Mt, suggesting that the interlayer space is more hydrated with Na+ as the interlayer space cation. Molecular dynamic simulations revealed a larger energy decrease when Cd2+ substitutes K+. However, the nice fit of the K+ into the 12-coordinated interlayer space sites may restrict its hydration and thus reduce its interlayer space cation exchange capability by Cd2+.