High-altitude (HA) natives have blunted ventilatory responses to hypoxia (HVR), but studies differ as to whether this blunting is lost when HA natives migrate to live at sea level (SL), possibly because HVR has been assessed with different durations of hypoxic exposure (acute vs. sustained). To investigate this, 50 HA natives (>3,500 m, for >20 yr) now resident at SL were compared with 50 SL natives as controls. Isocapnic HVR was assessed by using two protocols: protocol 1, progressive stepwise induction of hypoxia over 5-6 min; and protocol 2, sustained (20-min) hypoxia (end-tidal PO2 = 50 Torr). Acute HVR was assessed from both protocols, and sustained HVR from protocol 2. For HA natives, acute HVR was 79% [95% confidence interval (CI): 52-106%, P = not significant] of SL controls for protocol 1 and 74% (95% CI: 52-96%, P < 0.05) for protocol 2. By contrast, sustained HVR after 20-min hypoxia was only 30% (95% CI: -7-67%, P < 0.001) of SL control values. The persistent blunting of HVR of HA natives resident at SL is substantially less to acute than to sustained hypoxia, when hypoxic ventilatory depression can develop.