A standard murine model was used to determine whether acute pretreatment exposures to hypoxia could alter ultimate hypoxic survival time. Adult male albino mice (Mus musculus) weighing 25-30 g were subjected to three pretreatment hypoxic exposures (4.5% O2, balance N2) of increasing duration (90, 120, and 150 seconds) with 300 seconds of normoxia between each pretreatment exposure and before testing of hypoxic survival time. Acute pretreatment exposures to hypoxia significantly increased mean +/- SEM hypoxic survival time from 108 +/- 4 to 403 +/- 42 seconds. Mean +/- SEM blood glucose concentrations increased significantly from 201 +/- 19 to 397 +/- 10 mg/dl immediately after hypoxic pretreatment. A significant increase in mean +/- SEM blood ketone concentrations, from 0.15 +/- 0.01 to 0.40 +/- 0.08 mM, was detected in the blood 1,800 seconds but not 300 seconds after hypoxic pretreatment. However, pretreatment with exogenous glucose or ketones alone, to mimic the blood levels seen after hypoxic pretreatment, failed to increase hypoxic survival time. In contrast, mice pretreated with hypoxic exposures plus the exogenous substrate beta-hydroxybutyrate had an increased mean +/- SEM hypoxic survival time of 749 +/- 48 seconds and a decreased body temperature. Stepwise Cox regression analyses with body temperature as a fixed covariate suggest that this decrease in body temperature has a partial role in, but can not fully account for, the increased hypoxic survival time. These data suggest that sequential exposures to hypoxia induce metabolic changes that protect against the lethal effects of hypoxia, perhaps by altering substrate mobilization and utilization and/or by inducing a hypometabolic hypothermia.