INTRODUCTION In recent years there has been considerable interest on the use of gold nanoparticles (GNPs) as novel agents for cancer therapy, with many studies in diverse fields including preclinical and clinical trials . In particular, the use of GNPs showed promising results for cancerous cells radiosensitization at both kilo- and mega-voltage energies . As the concentration of nanoparticles increases the radiosensitization increases , both due to the higher number of photoelectric interactions, and consequently higher dose deposition, and to the additional oxidative stress induced by the presence of nanoparticles . Experimental studies have revealed that GNPs radiosensitization is also highly sensitive to photon source energy , cancer cell type , nanoparticle size and localization relative to cellular DNA . The premise of GNPs radiosensitization relies on the higher photoelectric absorption cross-section of gold relative to tissues. The high radiosensitization induced at kilovoltage energies by GNPs is well documented by both in vitro and in vivo studies (mice with implanted tumors) . However, the radiosensitization observed at kilovoltage energies by increased photoabsorption cannot help predict the effects occurring at clinically relevant megavoltage energies, where Compton interactions are dominant and photon energy absorption weakly depends on the atomic number. Ionization rates at megavoltage energies seem to be extremely low, meaning that, for doses typically used in radiotherapy, a fair amount of nanoparticles present in the system (_i.e._, more than 99% ) does not contribute to the dose deposition processes. Despite this minimal dose increase, it is was observed that GNPs could lead to significant levels of radiosensitization when irradiated with MV photons . Even for kV photons, the observed dose enhancement factor (DEF) cannot be completely justified only by the higher attenuation cross-section of gold relative to tissues (see for example ), and other mechanisms in addition to the strong photoelectric absorption have to be considered, such as different distributions of energy deposition at the nanometric scale, compared to those in tissues without GNPs , and/or additional oxidative stress induced by the nanoparticles presence . Additional studies are essential in order to understand the underlying processes of radiosensitization so as to use GNPs as a clinical therapeutic tool. In particular, the full mechanism under radiosensitization in radiotherapy still needs to be investigated in a patient-like geometry. Of note, the efficacy of a treatment depends on the nanoparticles concentration and spatial distribution in the tumor cells, as well as on the incident beam energy and delivered dose. When metallic nanoparticles are localized in the tumor a greater fraction of the incident photon energy can be imparted to it without escalating the damage to the surrounding healthy tissues. Since GNPs are easily synthesized and can be designed to interact with various biomolecules, improved diagnosis and treatments efficacy can be obtained by using labeled nanoparticles that target specific cell receptors. That is, it is expected that nanoparticles bound to targeting agents should accumulate in higher concentrations in the tumor than in other organs, therefore amplifying the dose release in the cancerous cells while keeping constrained the cellular damage in the surrounding healthy tissues. So far, GNPs uptake has been found to be highest when bound to sugars and peptides . It was also observed that, even in the absence of any surface modification, nanoparticles are able to passively accumulate in cancerous cells due to the enhanced permeability and retention effect (EPR) of the abnormal tumor microvasculature . The combined effects of the intrinsic passive targeting (EPR) with the actual functionalization of the particle surface providing active targeting highly improves GNPs concentration inside the tumor volume. In this paper, a radiobiological model is introduced to investigate the mechanisms underlying radiosensitization. The model, benchmarked with _in vitro_ data taken from the literature, was included in the simulations of breast cancer IMRT treatments, with both 6 and 15 MV photons. In these simulations different uptake scenarios were also modeled to quantify the expected effectiveness of radiotherapy treatments with GNPs targeted dose enhancement.