The reactions of trimethyl phosphate (TMP) have been studied extensively both in the gas phase and in solution. To complement the experimental studies and to gain insight into the factors influencing the site of reactivity, which can be either the carbon atom or phosphorus atom of TMP, we have carried out ab initio calculations to map out the gas-phase activation free energy profiles of the reactions of TMP with three anions, viz., (OH)(-), (CH3O)(-), and F-. The calculations reveal a novel activation free energy pathway for (OH)-attack of TMP in the gas phase: namely, nucleophilic addition at phosphorus, followed by pseudorotation and subsequent elimination with simultaneous intramolecular proton transfer. For the reaction of (OH)(-) with TMP at 298 K, nucleophilic substitution reaction at phosphorus is found to be competitive with and slightly faster than S(N)2 reaction at carbon. Both reactions yield the same products, (DMP)(-) and MeOH, consistent with the products observed experimentally. In the case of (OH)(-) and (CH3O)(-), entropy plays a significant role in addition to enthalpy in determining the site of reactivity of TMP in the gas phase; specifically, temperature-independent electrostatic forces favor attack at phosphorus, whereas temperature-dependent entropic factors bias attack toward carbon. Experiments are suggested to test the theoretical predictions.