Ferroportin (Fpn) is a transporter that releases Fe 2+ from cells and is important for iron homeostasis in circulation. Export of Fe 2+ by Fpn is coupled to import of H + to maintain charge balance. Although Ca 2+ was shown to modulate Fe 2+ transport in Fpn, transport of Ca 2+ by Fpn has not been demonstrated. Here we show that human Fpn (HsFpn) mediates Ca 2+ transport, and that the Ca 2+ transport does not rely on the transport of other ions. We determine the structure of Ca 2+ -bound HsFpn and identify a single Ca 2+ binding site distinct from the Fe 2+ binding sites. Further studies validate the Ca 2+ binding site and show that Ca 2+ transport is inhibited in the presence of Fe 2+ but not vice versa . Function of Fpn as a Ca 2+ uniporter in the absence of Fe 2+ provides a molecular basis for regulations of iron homeostasis by Ca 2+ .