MoSi2 is a promising high-temperature material with low density (6.3 g/cm3), high melting point (2020 °C), and good oxidation resistance at temperatures to about 1900 °C. However, in the intermediate temperature range between 400 and 600 °C, it is susceptible to a “pest” reaction which causes catastrophic disintegration by a combination of oxidation and fracture. In this study, we have used polycrystalline MoSi2, produced by arc-casting of the pure elements and by cold and hot pressing of alloy powders, to characterize the pest reaction and to determine the roles of composition, grain or phase boundaries, and physical defects on the oxidation and fracture of specimens exposed to air at 500 °C. It was found that pest disintegration occurs through transport of oxygen into the interior of the specimen along pre-existing cracks and/or pores, where it reacts to form MoO3 and SiO2. The internal stress produced during the formation of MoO3 results in disintegration to powder. Near the stoichiometric ratio, the susceptibility to pest disintegration increases with increasing molybdenum content and with decreasing density. Silicon-rich alloys were able to form protective SiO2 and showed no indication of disintegration, even at densities as low as 60%.