We examined the physiologic role of ferroportin (Fpn) in manganese (Mn) export using flatiron (ffe/+) mice, a genetic model of Fpn deficiency. Blood (0.0123 vs. 0.0107 mg/kg; P= 0.0003), hepatic (1.06 vs. 0.96 mg/kg; P= 0.0125), and bile Mn levels (79 vs. 38 mg/kg; P= 0.0204) were reduced in ffe/+ mice compared to+/+ controls. Erythrocyte Mn–superoxide dismutase was also reduced at 6 (0.154 vs. 0.096, P= 0.0101), 9 (0.131 vs. 0.089, P= 0.0162), and 16 weeks of age (0.170 vs. 0.090 units/mg protein/min; P< 0.0001). 54 Mn uptake after intragastric gavage was markedly reduced in ffe/+ mice (0.0187 vs. 0.0066% dose; P= 0.0243), while clearance of injected isotope was similar in ffe/+ and+/+ mice. These values were compared to intestinal absorption of 59 Fe, which was significantly reduced in ffe/+ mice (8.751 vs. 3.978% dose; P= 0.0458). The influence of the ffe mutation was examined in dopaminergic SH-SY5Y cells and human embryonic HEK293T cells. While expression of wild-type Fpn reversed Mn-induced cytotoxicity, ffe mutant H32R failed to confer protection. These combined results demonstrate that Fpn plays a central role in Mn transport and that flatiron mice provide an excellent genetic model to explore the role of this exporter in Mn homeostasis.—Seo, YA, Wessling-Resnick, M. Ferroportin deficiency impairs manganese metabolism in flatiron mice.