Total mercury (THg) was measured in muscle (fillet) and liver tissue of adult smallmouth bass Micropterus dolomieu collected at multiple sites in the Potomac and Susquehanna River drainages within the Chesapeake Bay watershed. Smallmouth bass in these drainages have experienced episodic mortality events, a high prevalence of skin lesions and reproductive endocrine disruption (intersex or testicular oocytes and plasma vitellogenin in males). A multi-level assessment of general and reproductive health including indicators at the organismal, organ, cellular and molecular levels was conducted on adult smallmouth bass during the spring (prespawn) season. Concentrations of THg were correlated with increased visible abnormalities, increased macrophage aggregates and tissue parasite burdens. In male bass positive correlations of THg were observed with plasma vitellogenin and hepatic transcript abundance of estrogen receptor β1 and androgen receptor α, while there was a negative association with estrogen receptors α and β2 and androgen receptors β. In female bass there was a negative correlation between THg and plasma vitellogenin as well as hepatic transcript abundance of vitellogenin, choriogenin, estrogen receptor β2 and 17β hydroxysteroid dehydrogenase. Associations of THg concentrations with various biological indicators suggest mercury may be an important environmental stressor contributing to the observed adverse effects in smallmouth bass populations.