The Belgian Material Test Reactor BR2 is a strongly heterogeneous high-flux engineering test reactor at SCK-CEN (Centre d'Etude de l'Energie Nucléaire) in Mol with a thermal power of 60 to 100 MW. It deploys highly enriched uranium, water-cooled concentric plate fuel elements, positioned inside a beryllium reflector with a complex hyperboloid arrangement of test holes. The objective of this paper is to validate the MCNP&ORIGEN-S three-dimensional (3-D) model for reactivity predictions of the entire BR2 core during reactor operation. We employ the Monte Carlo code MCNP-4C to evaluate the effective multiplication factor keff and 3-D space-dependent specific power distribution. The one-dimensional code ORIGEN-S is used to calculate the isotopic fuel depletion versus burnup and to prepare a database with depleted fuel compositions. The approach taken is to evaluate the 3-D power distribution at each time step and along with the database to evaluate the 3-D isotopic fuel depletion at the next step and to deduce the corresponding shim rod positions of the reactor operation. The capabilities of both codes are fully exploited without constraints on the number of involved isotope depletion chains or an increase of the computational time. The reactor has a complex operation, with important shutdowns between cycles, and its reactivity is strongly influenced by poisons, mainly 3He and 6Li from the beryllium reflector, and the burnable absorbers 149Sm and 10B in the fresh UAlx fuel. The computational predictions for the shim rod positions at various restarts are within 0.5 $ (eff = 0.0072).