Backsheet blistering in photovoltaic modules is frequently reported but not yet thoroughly described. Visual inspection only identifies the presence of bubbles, while physical mechanisms leading to their occurrence need further theoretical investigation. To evaluate the effect of external (temperature, humidity) and internal (manufacturing defects) causes of blistering, we propose a semi-analytic model to describe this phenomenon in poly(ethylene-co-vinyl acetate)-based modules. The blistering occurrence is triggered by pressure exerted by partially vaporized moisture in existing defects. Vapor pressure in such defects, originated during module manufacturing, is related to moisture concentration profiles, governed by external conditions. Moisture also affects the adhesive fracture energy which plays a fundamental role in blistering activation. The proposed model predicts the critical pressure and the critical size of the initial defects causing blistering. This work represents an important step for the long-term reliability prediction of photovoltaic modules.