The feasibility of producing 2000–3000 mCi 153Sm by irradiation of 152Sm in 5 MW TRR was studied via TRR core simulation. In this study the cross-section of 152Sm (n,γ) 153Sm reaction from ENDF/B library was used. The effective activation cross section for production of 153Sm is obtained using the neutron spectra in different irradiation channel of the core. The activity of the simulated samples is calculated using the obtained fluxes and cross sections. Then samples were prepared and irradiated under different conditions and fluxes. The final production’s specific activity was measured by the standard dose calibrator ISOMED 1010. By comparison of the theoretical calculations and actual measurements, an empirical correction factor (Kf) was obtained, which is helpful in production procedure of the 153Sm radioisotope. The optimal weight of the samples and irradiation time was studied according to the flux calculations based on the location of the sample and saturated activity calculation. In order to test the proposed conditions, samples were prepared and were irradiated under the proposed conditions. According to the compared results with the initial irradiation condition, the new proposed sample which weighed 4 mg of Sm2O3 is acceptable for the labeling, therefore this study led to nearly 60% decrease in the amount of material used in the production process.