The adrenocortical endocrine subsystem has been demonstrated to enhance mammalian tolerance to harsh environmental conditions, including hypoxia and temperature extremes. In a series of factorial experiments, mice were exposed to one of three elevated hydrostatic pressures for 30 min and then decompressed (0.75 atm/s). It was demonstrated that 1) tolerance to decompression does not differ significantly (P greater than 0.3) in surgically intact, sham adrenalectomized, or in adrenalectomized animals; 2) intraperitoneal administration of pharmacologic doses (0.4, 1.0, and 2.0 mg/mouse) or corticosterone or deoxycorticosterone acetate does not significantly enhance (P greater than 0.1) survivorship when compared to vehicle-injected controls; and 3) the incidence of decompression sickness (DS) does not fluctuate with time of day (P greater than 0.4). In a fourth study, the plasma concentration of corticosterone was quantitated in 1) colony control mice, 2) mice exposed to the 1-ATA chamber environment (chamber control), or 3) mice compressed to 3, 5, 7, 9, or 11 ATA and then decompressed. In general, plasma corticosterone in symptom-free mice was elevated approximately threefold (P less than 0.05) by exposure to the 1-ATA chamber environment and by decompression from 3 to 11 ATA. At 11 ATA, plasma corticosterone levels in decompressed mice exhibiting decompression sickness symptoms were significantly elevated (P less than 0.05) compared to the levels observed in decompressed symptom-free mice. These studies indicate that adrenocortical function does not enhance tolerance to decompression in mice.