This study has assessed the regulation of arterial blood and cerebrospinal fluid (CSF) pH and thereby their contribution to the control of breathing in normal man during various stages of ventilatory acclimatization to 3,100 m altitude. CSF acid-base status was determined: (a) from measurements of lumbar spinal fluid during steady-state conditions of chronic normoxia (250 m altitude) and at + 8 h and + 3-4 wk of hypobaric hypoxia; and (b) from changes in cerebral venous P_CO2 at + 1 h hypoxic exposure. After 3-4 wk at 3,100 m, CSF [H⁺] remained significantly alkaline to values obtained in either chronic normoxia or with 1 h hypoxic exposure and was compensated to the same extent (∼66%) as was arterial blood [H⁺]. Ventilatory acclimatization to 3,100 m bore no positive relationship to accompanying changes in arterial P_O2 and pH and CSF pH: (a) CSF pH either increased or remained constant at 8 h and at 3-4 wk hypoxic exposure, respectively, coincident with significant, progressive reductions in Pa_CO2; (b) arterial P_O2 and pH increased progressively with time of exposure; and (c) in the steady-state of acclimatization to 3,100 m the combination of chemical stimuli present, i.e. Pa_O2 = 60 mm Hg, pHa and pH_CSF = + 0.03-0.04 > control, was insufficient to produce the observed hyperventilation (Pa_CO2 = 32 mm Hg). It was postulated that ventilatory acclimatization to 3,100 m altitude was mediated by factors other than CSF [H⁺] and that the combination of chronic hypoxemia and hypocapnia of moderate degrees provided no mechanisms for the specific regulation of CSF [H_CO3⁻] and hence for homeostasis of CSF [H⁺].