1. In order to study the neuronal response to hypoxia with maturation, hypoglossal neurons from adult and neonatal rat (3-7, 14-16, 21 and 28 days) brain stem slices were subjected to O2 deprivation. All neurons depolarized and showed no evidence of hyperpolarization at any time during the hypoxic period. 2. The magnitude of depolarization was about three-fold larger in adult hypoglossal neurons (mean = 32.0 mV) than in young neonatal neurons (mean = 10.4-11.2 mV) during hypoxic exposure (15-20 Torr) of 5 min. During longer periods of hypoxia of 15-30 min, neonatal cells showed an increase in the magnitude of depolarization reaching a level close to 80% of that in the adult. 3. In the early phase of hypoxia, adult neurons increased peak and steady-state spike frequency to induced current injections. Later, both spike frequencies decreased and, in 1/2 of adult neurons, there was a depolarization block. Input resistance (RN) of most adult neurons increased during hypoxia (RN = 180% of control after 5 min). Though neonatal neurons increased firing frequency, none had depolarization block and there was no increase in RN. 4. Tetrodotoxin (TTX), tetraethylammonium (TEA), apamin, high Mg2+/low Ca2+ solutions and intracellular ethyleneglycol-bis-(beta-aminoethylether)N,N,N',N'-tetrac etic acid (EGTA) did not reduce the magnitude of depolarization in hypoglossal neurons of 4-week-old and adult rats. Strophanthidin application depolarized hypoglossal neurons but decreased RN. 5. Ion-selective electrodes used to measure K+ concentrations in the extracellular fluid (Ko+) revealed a major increase in Ko+ (mean = 3.2 mM) in the adult hypoglossal area but not in the newborn tissue (mean = 0.65 mM). This probably reflects a difference in the amount of K+ efflux between neonatal and adult hypoglossal neurons. Shrinkage in the extracellular compartment in the adult may also account for some of the difference. 6. These results suggest that neonatal neuronal tissue is more tolerant to hypoxia than the adult, with the inherent cellular properties being maintained in newborn but not in adult neurons. The difference in membrane depolarization during hypoxia between the neonate and the adult can be attributed, in part, to differences in Ko+. The reason(s) for the difference in Ko+ is not known but could be due, to some extent, to different rates of intracellular ATP depletion and failure of the Na(+)-K+ pump.