The current waste management strategy for spent nuclear fuel (SNF) mandated by the U.S. Congress is the disposal of high-level waste (HLW) in a geological repository at Yucca Mountain. Ongoing efforts on closed-fuel cycle options and difficulties in opening and safeguarding such a repository have led to investigations of alternative waste management strategies. One potential strategy would make use of fuels containing transuranic (TRU) nuclides in nuclear reactors. This would prolong reactor operation on a single fuel loading and by doing so, would reduce current HLW stockpiles. The analysis has already shown that high-temperature gas-cooled reactors (HTGRs) and their Generation IV extensions, very-high-temperature reactors (VHTRs), have encouraging performance characteristics that will allow for prolonged operation with no intermediate refueling, as well as for transmutation of TRUs. The objective of this research was to show that TRU-fueled VHTRs have the possibility of prolonged operation on a single fuel loading while retaining their Generation IV safety features. In addition, this research evaluated performance characteristics, and identified operational domains of these systems, as well as the possibility of HLW reduction. A whole-core, 3-D model of a power size prismatic VHTR with a detailed temperature distribution was developed for calculations with the SCALE 5.1 code package. Results of extensive criticality and depletion calculations with multiple fuel loadings showed that VHTRs are capable and suitable for autonomous operation when loaded with TRU fuel.