Cadmium (Cd) is an important environmental pollutant that can lead to impairment of cellular functions, energy misbalance and negatively impact survival in estuarine organisms including oysters. Like other marine bivalves, oysters can accumulate high Cd burdens in their tissues and are susceptible to the toxic effects of this metal. Presently, the factors that affect sensitivity to Cd toxicity and its variation in wild oyster populations are poorly understood. We analyzed geographical and seasonal variability of mitochondrial responses to elevated temperatures and Cd stress in eastern oysters Crassostrea virginica from populations adapted to different thermal regimes (subtropical Texas (TX), warm temperate North Carolina (NC) and cold temperate Washington (WA) areas). Seasonality had a strong effect on mitochondrial function in oysters from the two studied southern populations (TX and NC) but not in their northern (WA) counterparts, with decreased mitochondrial abundance and increased rates of mitochondrial proton leak in gill tissues of TX and NC oysters in summer. Compared to WA oysters, oysters from the two southern populations accumulated Cd faster in their tissues, and their mitochondria were more sensitive to Cd inhibition in resting and ADP-stimulated states at 20 and 28 degrees C. At 12 degrees C, inter-populational differences in Cd accumulation rates and sensitivity of mitochondrial respiration to Cd were not significant. Within each of the three studied populations, sensitivity of mitochondrial ADP-stimulated respiration to Cd inhibition increased with increasing temperatures (28>20>12 degrees C). This indicates that oysters from the two southern sites may be more vulnerable to Cd toxicity due to exposure to high environmental temperatures in summer, elevated rates of Cd accumulation and high intrinsic sensitivity of their mitochondria to Cd. This study suggests that data on sensitivity to pollutants obtained for one population of oysters should be extrapolated to other conspecific populations with caution and that regulatory standards for water pollution based on the studies from one geographical region may not be protective for other areas.