Ventilatory acclimatization to hypoxia (VAH) consists of a progressive increase in ventilation and decrease in end-tidal PCO₂ (PETCO₂). Underlying VAH, there are also increases in the acute ventilatory sensitivities to hypoxia and hypercapnia. To investigate whether these changes could be induced with very mild alterations in end-tidal PO₂ (PETO₂), two 5-day exposures were compared: 1) mild hypoxia, with PETO₂ held at 10 Torr below the subject's normal value; and 2) mild hyperoxia, with PETO₂ held at 10 Torr above the subject's normal value. During both exposures, PETCO₂ was uncontrolled. For each exposure, the entire protocol required measurements on 13 consecutive mornings: 3 mornings prior to the hypoxic/hyperoxic exposure, 5 mornings during the exposure and 5 mornings post exposure. After breathing room air for at least 30 min, measurements were made of PETCO₂, PETO₂ and the acute ventilatory sensitivities to hypoxia and hypercapnia. Ten subjects completed both protocols. There was a significant increase in the acute ventilatory sensitivity to hypoxia (Gp) following exposure to mild hypoxia, and a significant decrease in Gp following exposure to mild hyperoxia (p<0.05, repeated measures ANOVA). No other variables were affected by mild hypoxia/hyperoxia. The results, when combined with those from other studies, suggest that Gp varies linearly with PETO₂, with a sensitivity of 3.5±1.0 %/Torr (mean±SE). This sensitivity is sufficient to suggest that Gp is continuously varying in response to normal physiological fluctuations in PETO₂. We conclude that at least some of the mechanisms underlying VAH may have a physiological role at sea level.