Generation IV Very High Temperature Reactors (VHTRs) are well-known for their flexibility with respect to feasible fuel cycle options. In this paper, the LEU- and TRU-fueled VHTR configurations are analyzed accounting for their capabilities to attain an extended single-batch OTTO (Once-Through-Then-Out) mode of operation without intermediate refueling. The requirement of waste minimization is imposed as one of the design constraints defining possible system configurations and deployment strategies. The resulting "used fuel" vectors are examined considering anticipated disposal options as well as viability of fuel reprocessing. A Monte Carlo-deterministic analysis methodology has been implemented for coupled design studies of VHTRs with TRUs using the ORNL SCALE 5.1 code system. The developed modeling approach provides an exact-geometry 3D representation of the VHTR core details properly capturing VHTR physics. The presented analysis is focused on prismatic block core concepts for VHTRs. It is being performed within the scope of the U.S. DOE NERI project on utilization of higher actinides (TRUs and partitioned MAs) as a fuel component for extended-life VHTR configurations. © 2010 Elsevier B.V. All rights reserved.