Gold nanoparticles can be used to increase the dose of the tumor due to its high atomic number as well as being free from apparent toxicity. The aim of this study is to evaluate the effect of distribution of gold nanoparticles models, as well as changes in nanoparticle sizes and spectrum of radiation energy along with the effects of nanoparticle penetration into surrounding tissues in dose enhancement factor DEF. Three mathematical models were considered for distribution of gold nanoparticles in the tumor, such as 1-uniform, 2- non-uniform distribution with no penetration margin and 3- non-uniform distribution with penetration margin of 2.7 mm of gold nanoparticles. For this purpose, a cube-shaped water phantom of 50 cm size in each side and a cube with 1 cm side placed at depth of 2 cm below the upper surface of the cubic phantom as the tumor was defined, and then 3 models of nanoparticle distribution were modeled. MCNPX code was used to simulate 3 distribution models. DEF was evaluated for sizes of 20, 25, 30, 50, 70, 90 and 100 nm of gold nanoparticles, and 50, 95, 250 keV and 4 MeV photon energies. In uniform distribution model the maximum DEF was observed at 100 nm and 50 keV being equal to 2.90, in non-uniform distribution with no penetration margin, the maximum DEF was measured at 100 nm and 50 keV being 1.69, and in non-uniform distribution with penetration margin of 2.7 mm, the maximum DEF was measured at 100 nm and 50 keV as 1.38, and the results have been showed that the dose was increased by injecting nanoparticles into the tumor. It is concluded that the highest DEF could be achieved in low energy photons and larger sizes of nanoparticles. Non-uniform distribution of gold nanoparticles can increase the dose and also decrease the DEF in comparison with the uniform distribution. The non-uniform distribution of nanoparticles with penetration margin showed a lower DEF than the non-uniform distribution without any margin and uniform distribution. Meanwhile, utilization of the real X-ray spectrum brought about a smaller DEF in comparison to mono-energetic X-ray photons.