A 16-yr-old, captive-born, female California sea lion (Zalophus californianus) was evaluated for intermittent lethargy, partial anorexia, and polydipsia of 2 wk duration. The animal was immobilized for physical examination. It was in thin body condition, with multifocal mucosal ulcerations over the caudal and ventral tongue. Blood was collected for hematology, serum chemistry, and leptospirosis serology. Serum chemistry revealed severe azotemia, mild hyperglycemia, and severe hyperphosphatemia. The animal went into cardiac arrest during recovery from anesthesia and died. On histopathology, abundant amorphous, finely fibrillar, eosinophilic material was deposited in the kidneys, and smaller amounts of the same material were found in the splenic and pancreatic vessels; these findings are consistent with systemic secondary amyloidosis. The animal also had chronic nephritis, which, coupled with renal amyloidosis, resulted in renal failure and death. Systemic amyloidosis should be considered as an additional differential diagnosis for renal failure in California sea lions.