Purpose: Multicellular tumor spheroids are realistic in-vitro systems used in radiation biology research to studythe effect of anticancer drugs or to evaluate the resistance of cancer cells under specific conditions. Whencombining the modeling of spheroids together with the simulation of radiation using Monte Carlo methods, onecould estimate cell and DNA damage to be compared with experimental data. We developed a Cell Population(CPOP) modeler combined to Geant4 simulations in order to tackle how energy depositions are allocated to cells,especially when enhancing radiation outcomes using high-Z nanoparticles. CPOP manages to model large threedimensionalcell populations with independent deformable cells described with their nucleus, cytoplasm andmembranes together with force law systems to manage cell–cell interactions.Methods: CPOP is an opensource platform written in C++. It is divided into two main libraries: a “Modeler”library, for cell geometry modeling using meshes, and a Multi Agent System (MAS) library, simulating all agent(cell) interactions among the population. CPOP is fully interfaced with the Geant4 Monte Carlo toolkit and is ableto directly launch Geant4 simulations after compilation.We modeled a full and realistic 3D cell population from SK-MEL28 melanoma cell population cultured experimentally.The spheroid diameter of 550 ± 40 μm corresponds to a population of approximately 1000 cells havinga diameter of 17.2 ± 2.5 μm and a nucleus diameter of 11.2 ± 2.0 μm. We decided to reproduce cell irradiationsperformed with a X-RAD 320 Biological Irradiator (Precision XRay Inc., North Branford, CT).Results: We simulated the energy spectrum of secondary particles generated in the vicinity of the spheroid andplotted the different energy spectra recovered internally to the spheroid. We evaluated also the impact of AGuIX(Gadolinium) nanoparticles modeled into the spheroid with their corresponding secondary energy spectra.Conclusions: We succeeded into modeling cell populations and combined them with Geant4 simulations. The nextstep will be to integrate DNA geometrical models into cell nuclei and to use the Geant4-DNA physics andradiolysis modeling capabilities in order to evaluate early strand breaks induced on DNA.