OBJECTIVE A markedly elevated serum ferritin level has been associated with inflammatory conditions such as adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Hyperferritinemia, however, can also be caused by a wide variety of disparate conditions, often with impressively high serum levels. The objective of this analysis was to investigate the underlying etiology of markedly elevated ferritin levels in a large group of patients treated as outpatients and inpatients in a tertiary-care medical center. METHODS Data of all adult patients from 2008 through 2010 with at least 1 serum ferritin level greater than 1000 μg/L were reviewed. If a patient had multiple qualifying levels, the highest one was used. For each case, the most likely cause of the elevated ferritin was assessed based on the available clinical data using a simple algorithmic approach. RESULTS Six hundred twenty-seven patients were found. The average serum ferritin level was 2647 μg/L. The most frequent condition was malignancy (153/627), with iron-overload syndromes the second most common (136/627). There were 6 cases of adult-onset Still's disease, systemic juvenile idiopathic arthritis, or hemophagocytic lymphohistiocytosis/macrophage activation syndrome. The average ferritin level in these syndromes was 14242 μg/L. Seven patients appeared to have anemia of chronic inflammation, and in 5 patients, there was no clearly definable cause for hyperferritinemia. CONCLUSIONS Although extremely elevated ferritin levels may be associated with rheumatologic diseases, more often they are found in patients with other conditions such as malignancy or infection. In addition, extremely high ferritin levels can be found in patients with seemingly indolent disease or levels of chronic inflammation.