There is considerable evidence that consuming fish has numerous health benefits, including a reduced risk of cardiovascular disease. However, fish is also the primary source of human exposure to mercury (Hg). In a cross-sectional study of 9–11 year old children (N¼100), we measured fish consumption, blood lipids, total blood Hg, diurnal salivary cortisol (4 samples collected throughout the day), and performed a proteomic analysis of serum proteins using spectral count shotgun proteomics. Children who consumed fish had a significantly more atheroprotective lipid profile but higher levels of blood Hg relative to children that did not consume fish. Although the levels of blood Hg were very low in these children (M¼0.77 mg/L; all but 1 participant had levels below 3.27 mg/L), increasing blood Hg was significantly associated with blunted diurnal cortisol levels. Blood Hg was also significantly associated with acute-phase proteins suggesting systemic inflammation, and several of these proteins were found to significantly reduce the association between Hg and diminished cortisol when included in the model. This study of a pediatric population is the first to document an association between blood Hg, systemic inflammation, and endocrine disruption in humans. Without a better understanding of the long-term consequences of an atheroprotective lipid profile relative to blunted diurnal cortisol and systemic inflammation, a determination of the risk-benefit ratio for fish consumption by children is not possible. © 2011 Elsevier Inc. All rights reserved.