Previously it was not possible to predict reliably the rate at which spent fuel would react with groundwater because of conflicting data in the literature. The dissolution of the UO2 spent fuel matrix is a necessary step for aqueous release of radioactive fission products. Statistical experimental design was used to plan a set of UO2 dissolution experiments to examine systematically the effects of temperature (25-75°C), dissolved oxygen (0.002-0.2 atm overpressure), pH (8-10) and carbonate (2-200x10-4 molar) concentrations on UO2 dissolution. The average dissolution rate was 4.3 mg/m2/day. The regression fit of the data indicate an Arrhenius type activation energy of -8750 cal/mol·K and a half-power dependence on dissolved oxygen in the simulated groundwater.