Sustainable and safe energy supply with High Temperature Gas-cooled Reactor (HTGR) fueled by uranium from seawater have been investigated and discussed. From the view point of safety feature of self-regulation with thermal reactor of HTGR, the uranium resources should be inexhaustible. The seawater uranium is expected to be alternative resources to conventional resources because it exists so much in seawater as a solute. It is said that 4.5 billion tons of uranium is dissolved in the seawater, which corresponds to a consumption of approximately 72 thousand years. Moreover, a thousand times of the amount of 4.5 trillion tU of uranium, which corresponds to the consumption of 72 million years, also is included in the rock on the surface of the sea floor, and that is also recoverable as seawater uranium because uranium in seawater is in an equilibrium state with that. In other words, the uranium from seawater is almost inexhaustible natural resource. However, the recovery cost with current technology is still expensive compared with that of conventional uranium. Then, we assessed the effect of increase in uranium purchase cost on the entire electricity generation cost. In this study, the economy of electricity generation of cost of a commercial HTGR was evaluated with conventional uranium and seawater uranium. Compared with ordinary LWR using conventional uranium, HTGR can generate electricity cheaply because of small volume of simple direct gas turbine system compared with water and steam systems of LWR, rationalization by modularizing, and high thermal efficiency, even if fueled by seawater uranium.