Reactive oxygen species favor the reductive state of iron. Antioxidation, by depleting biologically active ferrous iron, could then have a stabilizing effect, akin to hypoxia, on HIF-1α; the process which controls the genetic responses to hypoxia. However, the influence of antioxidation on the hypoxic ventilatory responses (HVR) is unclear. In this study we set out to determine the influence of mangiferin, a natural polyphenolic compound present in mango trees, with strong antioxidant and iron chelating properties, on the HVR. The study was performed in awake Wistar rats. Acute HVR to 12% and 8% FiO(2) before and 40 min after mangiferin (300 mg/kg, i.p.) pretreatment were recorded plethysmographically. We found that mangiferin significantly dampened the HVR over its course. To distinguish between the scavenging and chelating mechanisms of mangiferin we reinvestigated its effects on the HVR in a separate group of rats after chronic antecedent iron chelation with ciclopirox olamine (20 mg/kg daily for 1 week). The dampening effect on the HVR of mangiferin was preserved in the pre-chelated rats, which points to the preponderance of the antioxidant over chelating properties of mangiferin in its ventilatory effects. Although the exact determinants of mangiferin action remain unclear, the study suggests a role for oxidative signaling in the peripheral chemosensory processing of the HVR. The study also implies the possible clinical use of the antioxidant mangiferin in the regulation of lung ventilation.