Infectious diseases have been implicated as a cause of high rates of adult mortality in southern sea otters. Exposure to environmental contaminants can compromise the immuno-competence of animals, predisposing them to infectious diseases. In addition to organic pollutants, certain trace elements can modulate the immune system in marine mammals. Nevertheless, reports of occurrence of trace elements, including toxic heavy metals, in sea otters are not available. In this study, concentrations of 20 trace elements (V, Cr, Mn, Co, Cu, Zn, Rb, Sr, Mo, Ag, Cd, In, Sn, Sb, Cs, Ba, Hg, Tl, Pb, and Bi) were measured in livers of southern sea otters found dead along the central California coast (n = 80) from 1992 to 2002. Hepatic concentrations of trace elements were compared among sea otters that died from infectious diseases (n = 27), those that died from non-infectious causes (n = 26), and otters that died in emaciated condition with no evidence of another cause of death (n = 27). Concentrations of essential elements in sea otters varied within an order of magnitude, whereas concentrations of non-essential elements varied by two to five orders of magnitude. Hepatic concentrations of Cu and Cd were 10- to 100-fold higher in the sea otters in this study than concentrations reported for any other marine mammal species. Concentrations of Mn, Co, Zn, and Cd were elevated in the diseased and emaciated sea otters relative to the non-diseased sea otters. Elevated concentrations of essential elements such as Mn, Zn, and Co in the diseased/emaciated sea otters suggest that induction of synthesis of metallothionein and superoxide dismutase (SOD) enzyme is occurring in these animals, as a means of protecting the cells from oxidative stress-related injuries. Trace element profiles in diseased and emaciated sea otters suggest that oxidative stress mediates the perturbation of essential-element concentrations. Elevated concentrations of toxic metals such as Cd, in addition to several other organic pollutants, may contribute to oxidative stress-meditated effects in sea otters.