To determine whether a rightward shift of the ODC was beneficial for short-term high-altitude adaptation, 10 drug-treated subjects were compared in a double-blind manner to 10 placebo-treated subjects after ascent from Ann Arbor, Mich. (240 m) to the top of Pike's Peak, Colo. (4300 m). Subjects were normal, male residents at 240 m in good health. Phosphate (30 mmol, t.i.d.), vitamin C (500 mg, q.i.d.), and sodium bicarbonate (1.25 mEq/kg body weight) were administered in order to elevate 2,3-DPG levels and shift ODCs to the right before the ascent so that subjects with right-shifted ODCs could be contrasted with subjects whose ODCs were not right-shifted during the first 1 to 2 days at 4300 m. After 24 hr at 4300 m, 2,3-DPG levels were higher in drug-treated than in placebo-treated subjects (19.7 +/- 0.6 mmol/gm of hemoglobin vs. 18.5 +/- 0.4; p less than 0.05 by one-tailed test), and ODC positions were different after 6 hr at high altitude (one-tailed p less than 0.01). Drug-treated subjects felt better as measured by a symptomatology questionnaire and had better central nervous system function as measured by a darkness-adaptation visual task. Performance in the two groups of subjects was the same on other visual and cognitive psychometric tests. Cardiopulmonary responses to high altitude were comparable in the two groups. The small, though significant improvement in dark adaptation and symptoms in drug-treated subjects suggests that oxygenation of the brain may have benefited from the small-shift in ODC observed. Agents with greater effect on 2,3-DPG levels are deserving of trial to determine whether they have more substantial effects on short-term responses to high altitude.