The hypothesis that elevated levels of ammonia-releasing compounds in tobacco and ammonia in mainstream (MS) smoke increase the rate and amount of nicotine evaporation from the particles of MS smoke aerosol was examined by kinetic modeling and experiments with MS cigarette smoke. Computational simulation of a kinetic mechanism describing volatile loss of nicotine, ammonia, and acetic acid from an aqueous solution was used to compute the time-dependent concentration of all species in the model. Because of the high volatility of ammonia relative to that of nicotine, variation over a wide range of initial ammonia concentration had no significant effect upon the rate of loss of nicotine from the model system. The effects of a variation in the volatile loss rate constant for ammonia and for the acid were examined. The simulations show that ammonia is lost from the model solution at a greater rate than nicotine and acid, and the loss of volatile acid has a significant role in the rate and amount of nicotine loss. Simulations with a model system undergoing a continuous steady addition of ammonia showed that high rates of ammonia addition could significantly increase the rate of nicotine volatile loss from the model solution. A series of smoking experiments was performed using blended cigarettes connected to a denuder tube. Deposition of smoke constituents can occur directly from the gas phase and by the deposition of smoke aerosol particles themselves. As nicotine exists >99% in the particle phase of MS smoke, in the absence of particle deposition, denuder tube deposition of nicotine occurs via the evaporation−deposition pathway. Solanesol, a nonvolatile tobacco and smoke terpene, was used to quantify the amount of particle deposition onto the denuder tube. The amount of ammonia deposited on the denuder tube was an order of magnitude greater than that of nicotine, showing that ammonia evaporates from the MS smoke particles much faster than does nicotine. The experimental results were supported and explained by the aqueous model simulations. Included in these experiments are cigarettes that differ in their MS smoke ammonia content by a factor of ca. five. However, an increased amount of MS smoke ammonia does not increase the rate of nicotine loss from the particles. The combined results support the conclusion that ammonia in mainstream smoke has little effect, if any, upon the rate and amount of nicotine evaporation from MS smoke particles.