Deferoxamine has been proposed as a potentially important therapy for individuals with NIDDM and mild elevations in serum ferritin. Previously, iron chelation therapy with intravenous deferoxamine over a 5-13-wk period has been reported to normalize serum ferritin and markedly improve glycemic control. To confirm these results and to study potential beneficial effects of deferoxamine on insulin secretion, 9 individuals with NIDDM and elevated serum ferritin levels were treated twice weekly with deferoxamine infusion, following a previously described protocol. Although 8 of 9 subjects achieved normal or near-normal serum ferritin values after deferoxamine therapy, we found little evidence that it produced beneficial effects on glycemic control. Fasting glucose levels pre- and post-deferoxamine therapy were unchanged (11.6 ± 1.2 and 11.3 ± 1.5 mM, respectively, P = 0.80). GHb levels declined slightly after deferoxamine therapy (9.3 ± 0.7 vs. 8.8 ± 0.7%, P < 0.05); however, this effect was small and was not associated with elimination of or even substantial reduction in insulin or oral hypoglycemic therapy. Deferoxamine therapy did not significantly alter fasting insulin or C-peptide levels, nor stimulated insulin or C-peptide responses to intravenous arginine or glucose. During follow-up studies 1.5-8 mo after deferoxamine therapy, serum ferritin levels again were elevated in 5 of 8 subjects who showed an initial response. Thus, although deferoxamine therapy reduced serum ferritin levels in our subjects, we were unable to confirm a previous report that this effect was associated with any meaningful improvement in glycemic control or insulin secretion.