This work addresses the impact of radiation damage on the leaching of International Simple Glass (ISG). Pristine glass and specimens irradiated with multienergy Au ions were leached for 82 days at 90 °C in pure water and pH 9 and regularly sampled. Samples leached for 13 and 58 days were characterized using transmission electron microscopy (TEM) to study the microstructure(s) of the alteration layers formed from the radiation-damaged and pristine glasses. Furthermore, a sample altered for 82 days was immersed in water enriched in isotopically tagged water molecules (H2 18O) to study and compare the mobility and reactivity of water at room temperature in the alteration layers formed on these glasses. The studies revealed that radiation damage diminished the chemical durability of the ISG since the beginning of the leaching experiment. Concomitantly, the formation of a nonporous alteration layer of about 237 nm after 13 days of leaching evolving into the formation of a nanoporous alteration layer of about 570 nm after 58 days of leaching was observed in the irradiated glasses. In contrast, a nonporous altered layer of about 138 nm only developed in the non-irradiated specimen altered for 58 days. Using energy-filtered transmission electron microscopy, the altered layers in all cases were found to be depleted in boron, in agreement with the time-of-flight secondary ion mass spectroscopy studies. Despite pore formation, similar behavior in the 18O-16O exchanges (with respect to the uncertainties) was observed in the major part of the alteration layers whether formed from the irradiated or pristine ISG, leading to the conclusion that the greater alterability of the radiation-damaged ISG may not be due to the porosity. However, isotopic exchanges also revealed a significantly higher reactivity of water in the alteration-layer/glass interface for the irradiated glass. While these studies provide important insights about the role of porosity and radiation damages, they also highlight the complex nature of glass dissolution and suggest that studies directed at the alteration-layer/glass interface are needed to better understand and explain the mechanisms controlling the glass dissolution in the residual alteration rate regime.