1H AND 31P NUCLEAR magnetic resonance (NMR) spectroscopy were used to study the role of external pH (pH) in regulation of intracellular pH (pH) in the cerebral cortex in vitro. Lowering the pH of the oxygenated superfusion medium (pHb) from 7.5 to 7.0–6.8 decreased pHi from 7.33 ± 0.08 to $7.00 independently of the presence of HCO3- Following and medium buffering power. Reduction of medium (pHb 6.8) buffering power during hypoxia severely acidified pHi independently of the pressence of HCO3-. Following hypoxia, recovery of pHi was not sensitive to pHb provided that medium buffering was maintained. Lactate removal proceeded independently of pHb, HCO−3 and external buffering power. These results indicate that decrease in extracellular buffering capacity has a feed-back effect on pHi in the cerebral cortex.