The effects of pentobarbital on survival times of mice exposed to oxygen, 5 per cent, were studied over a large dosage range in normal mice and in mice made tolerant to the effect of barbiturates. Tolerance was induced by pretreatment with phenobarbital, 210 mg/kg, for three days, which increased the median anesthetic dose (AD50) for pentobarbital from 34 to 53 mg/kg. In nontolerant mice there was a dose-related increase in mean survival times for doses between 35 and 60 mg/kg, with a maximum increase to 303 per cent above control. At doses of more than 60 mg/kg survival times progressively decreased toward control. For tolerant mice survival time as a function of pentobarbital dosage was shifted to the right, i.e., protection necessitated higher doses. This shift was not explained by lower brain concentrations of pentobarbital in tolerant animals, but rather parallelled the increased tolerance to the anesthetic effect of the barbiturate. The authors conclude that in this model the protective effect of barbiturate is a function of the anesthetic effect rather than the barbiturate concentration in brain per se. Hypothermia (29 C) resulted in an increase in mean survival time comparable to that in barbiturate-treated animals. This supports the hypothesis that protection is ultimately a function of decreased cerebral metabolism, whether produced by anesthesia or by hypothermia. This model measures only the effect on spontaneous respiration during hypoxia. It is possible that other mechanisms are involved if barbiturates protect in other situations, such as during or after periods of complete ischemia.