The production of Mo-99, I-131, and Xe-133 radionuclides is very important for consumption in the field of nuclear medicine. Generally, the use of small core reactors is recommended for the production of large-scale these fission radionuclides. In this paper, we have considered three different core loading patterns of Tehran Research Reactor for the economic and optimum production of Mo-99, I-131 and Xe-133 from low-enriched uranium. These patterns are the large core, the small core with beryllium reflector (SC-Be), and the small core with graphite reflector. Simulation has been performed by MCNPX2.6 to compute the safety calculations, neutron flux changes, and evaluation of mentioned radionuclides production. The results reveal that the SC-Be is more suitable than the others two, in terms of safety. In this core, the drop of thermal neutron flux after loading the mini-plate targets is 11% and the activity of Mo-99, I-131, and Xe-133 is 235, 227, and 592 Ci, respectively, at the 8 days after the end of irradiation. So, if the changing pattern of the small core is considered, the SC-Be should be suggested.