To determine the effect of natural exposure to domoic acid (DA) on eosinophil counts and adrenal gland function in California sea lions (Zalophus californianus). Cross-sectional prospective study. 39 California sea lions. Adult female sea lions admitted to a rehabilitation hospital during 2009 were classified into 1 of 3 groups (acute DA toxicosis, chronic DA toxicosis, or no DA exposure) on the basis of clinical signs, DA concentration in urine or feces, and hippocampal morphology. Endoparasite burden, eosinophil count, and serum cortisol and plasma ACTH concentrations were determined for each sea lion. For a subset of 8 sea lions, fecal glucocorticoid concentration after IM administration of cosyntropin was determined. Sea lions exposed to DA (acute DA toxicosis, n = 11; chronic DA toxicosis, 19) had higher eosinophil counts and lower serum cortisol concentrations, compared with values for sea lions with no DA exposure (9). Eosinophil count was not associated with endoparasite burden. Serum cortisol concentration was associated with plasma ACTH concentrations in sea lions from the no DA exposure group but not in sea lions in the acute or chronic DA toxicosis groups. Following cosyntropin injection, fecal glucocorticoid concentrations increased in all sea lions evaluated except 1. In adult sea lions, eosinophilia may be a cost-effective biomarker for DA exposure and may reflect alterations in hypothalamic, pituitary gland, or adrenal gland function. Domoic acid exposure may have subtle health effects on marine animals in addition to induction of neurologic signs.