We investigated the microstructural response of molybdenum, with and without prior exposure to gaseous deuterium, during helium irradiation and subsequent annealing. Ion irradiations and annealing experiments were performed in situ in a transmission electron microscope, enabling real time observation of the microstructural evolution. Cavities approximately 0.5 nm in diameter were formed in deuterium-exposed molybdenum at a fluence of 1.7 × 1015 helium cm−2, but did not grow appreciably after increasing the fluence by two orders of magnitude or after brief room temperature aging. Similar cavities were not apparent in pristine molybdenum. Larger cavities appeared in both samples during in situ annealing to 1063 K, without any clear differences between the two samples. The evolving cavity morphologies are discussed in terms of defect production, microstructure, and sample geometry.