Mass mortality is often observed in cultured oysters during the period following spawning in the summer season. To examine the underlying causes leading to this phenomenon, thermotolerance of the Pacific oyster Crassostrea gigas was assessed using pre- and postspawning oysters that were sequentially treated with sublethal (37°C) and lethal heat shocks (44°C). The effects were examined on a range of immune and metabolic parameters in addition to mortality rate. A preventative 37°C significantly reduced oyster mortality after exposure to a second heat shock of 44°C, but in postspawning oysters mortality remained at 80%, compared with < 10% in prespawning oysters. Levels of the 72 kDa and 69 kDa heat shock proteins were low in the gill tissue from postspawning oysters stimulated by heat shock, indicating spawning reduced heat shock protein synthesis. The postspawning oysters had depleted glycogen stores in the mantle tissue and reduced adenylate energy charge after heat shock, indicative of lower energy for metabolic activity. A cumulative effect of spawning and heat shock was observed on the immunocompetence of oysters, demonstrated by reduced hemocyte phagocytosis and hemolymph antimicrobial activity. These results support the hypothesis that the energy expended during reproduction compromises the thermotolerance and immune status of oysters, leaving them easily subject to mortality if heat stress occurs in postspawning stage. This study improves our understanding of oyster summer mortality and has implications for the long-term persistence of mollusks under the influence of global warming.