The aldosterone and cortisol responses to small doses of ACTH (0.125, 0.25, 0.5, and 1.25 micrograms) after dexamethasone administration were measured in normal subjects at sea level while breathing room air (mean O2 saturation, 97 +/- 0.9%) and again while breathing hypoxic gas to lower the O2 saturation to 90%. A population of subjects matched for age and sex adapted to 3000 meters above sea level living in Colombia, South America, was also studied (mean O2 saturation, 94 +/- 0.7%). Hypoxemia, either induced at sea level or as a consequence of high altitude living, resulted in significant inhibition of aldosterone secretion after progressive administration of increasing doses of ACTH, but did not affect the cortisol response to ACTH. In addition, it was associated with higher plasma atrial natriuretic hormone levels. PRA declined only during acute hypoxemia induced at sea level and did not change during sea level normoxemia or high altitude living. Plasma sodium and potassium concentrations were no different in the three experimental conditions. We conclude that hypoxemia inhibits ACTH-stimulated aldosterone secretion and speculate that atrial natriuretic hormone may have mediated this effect.