Poland is the most coal-dependent economy and one of the biggest polluters in the EU. In order to alleviate this problem, meet CO2 emission requirements set by EU, and improve the country’s energy security, Poland decided to introduce nuclear power to its energy mix. So far, several potential locations for nuclear power plants have been officially proposed, mainly based on technical parameters, but no comparisons of the economic impact of such locations have been considered. Consequently, the main goal of this paper is to compare the national and regional economic effects of investments in nuclear power plants—for both the construction and exploitation phases—in the four most probable locations, which are similarly beneficial from a technical point of view. In order to simulate these effects, the spatial recursive dynamic Computable General Equilibrium model was calibrated until 2050 including agglomeration effects and featuring the regional economies of all Polish regions. The results show that although the construction phase is beneficial for economic development in all four regions, the exploitation phase is good for only one. The economies of the other regions suffer, to a greater or lesser extent, from the Dutch disease. The paper argues that the regional economic effects of such an investment differ significantly, due to differences in the regions’ economic structures; hence, they should always be taken into account in the final decisions on the power plants’ locations.