To identify the relationship between mercury (Hg) and stress responses in the clam Mactra veneriformis, metallothionein (MT) and superoxide dismutase (SOD) mRNA expression in the digestive gland, gill, and mantle as well as MT protein content and SOD activity in the digestive gland were examined under sublethal Hg exposure at doses of 10, 20, and 40 μg/L for 21 days. The ranking of the tissues in decreasing order of their basal MvMT and MvSOD mRNA expression is as follows: digestive gland > mantle > gill > adductor muscle > foot and digestive gland > mantle > gill > foot > adductor muscle, respectively. Hg exposure significantly elevated MvMT and MvSOD mRNA transcripts in the digestive gland, gill, and mantle in a tissue-specific way. In the digestive gland, a dose-dependent increase of MvMT and MvSOD mRNA expression, stimulation of MT protein, and alteration of SOD activity were observed under Hg stress. MT protein responded later than MT mRNA to Hg exposure and no clear relationship was found between them, indicating the occurrence of posttranscriptional events. All of the results suggest that MT and SOD cooperate in resisting Hg toxicity and maintaining cellular metabolic homeostasis in M. veneriformis. MT and SOD mRNA expressions have great potential as biomarkers of Hg pollution in the aquatic environment for the studied species.