In the present study, computational fluid dynamics (CFD) simulations of airflow in turbulent conditions and forced convection heat transfer inside a reprocessed fuel storage vault have been carried out. Full-scale simulations of airflow hydrodynamic inside the vault, which consists of a blanket and a fuel enclosure connected by a series of S-shaped interconnecting ducts was investigated. Different turbulent models were compared and the standard k-ε model was chosen based on its accuracy and faster convergence. The effect of triangular and square pitch arrangement of fuels and blankets on ventilation performance was analyzed in terms of temperature and velocity distributions of air. The triangular pitch arrangement of the fuels and blankets offered greater resistance to airflow resulting in decrease in average velocity of the air. This led to a slight increase in the temperature of fuel subassemblies and magazines. The temperature of fuels and hot spots in square pitch arrangement was much lower than those in triangular pitch arrangement. The ventilation performance of the vault was also analyzed in terms of thermal effectiveness and air exchange rate.