The Pacific oyster Crassostrea gigas (Thunberg, 1793) is an important part of the aquaculture industry in Europe; however, since 2008, oyster mortality events (>20%) have become a regular summer occurrence. This study monitored and recorded C. gigas mortality events during a 3-y period at a commercial oyster site in Lough Foyle, North of Ireland, and related these to environmental conditions, oyster physiology, and husbandry practices. Early summer temperature rises above 16°C were consistently correlated with large mortality events, but warmer temperatures in late summer did not cause mortalities, including in 1 y when there were no early summer mortalities. Mortalities were also correlated with a sharp early summer decrease in salinity from 22.2 to 16.9. In the laboratory, the combined effects of various temperatures and salinities on oyster stress levels were investigated using total hemocyte count and neutral red retention techniques. The cell membrane integrity and hemocyte density in C. gigas are sensitive to temperatures of 20°C or greater and at salinities of 20 or lower. This suggests that high temperature and low salinity combinations can negatively impact oyster stress levels and potentially increase oyster vulnerability to infections, including oyster herpes OsHV-1 µvar. Comparing survivorship in experimental bags simulating commercial growing conditions, these results equivocally support previous studies in which higher shore position was correlated with higher survivorship. Bags of oysters at lower density in lower shore positions were equally successful and may be more protected from climate-related stressors. Focusing on a single stressor is insufficient to predict future oyster mortalities, but balancing effects and relieving stress on oyster stocks through husbandry could limit the impacts of summer mortalities.