This paper deals with the theoretical foundation to estimate the relative efficiency (probability of inferring the true tree) of different nucleotide substitution models. A novel theoretical approach has been developed to estimate the relative efficiency of nucleotide substitution models based on the neighbor-relation method. The theory was developed directly by using the four-point condition. Initially theoretical formulas for the Jukes-Cantor+gamma (JC+Gamma) model and the Jukes-Cantor (JC) model were developed to estimate their relative efficiencies. Theoretical formulas were used on several model topologies for both models to obtain a true tree. Extensive simulations were performed on the same set of trees to test the strength of the theoretical approach. Simulation results demonstrated a good agreement with results obtained by the theoretical estimation. Overall the theoretical foundation for estimating model efficiencies is very accurate.