AY-9944, a cholesterol biosynthesis inhibitor, reduces adrenal corticosteroid production and may accelerate pulmonary surfactant production. Divided into four experimental groups were 130 male 100-g, 5-week-old Wistar-Lewis rats. Group 1 received no injections. Group 2 received 0.5 ml N NaCl ip qd times 21 d, and Group 3 received 1.5 mg AY-9944 in 0.5 ml N NaCl ip qd times 21 d. Group 4 animals received 5.0 mg hydrocortisone phosphate in 0.5 ml N NaCl sc qd times 7 d. All injections were done prior to exposing the animals to 98-99 plus % oxygen at 1 atmospheric pressure (OAP) for varying lengths of time. AY-9944 treatment resulted in a significant (p smaller than 0.05) reduction in body growth by Day 7 when compared to saline-injected litter-mates. By Day 21 this difference was highly significant (p equals 0.00002). Lungs from AY-9944 treated rats were heavier than the lungs from the other groups. Surprisingly, there were no differences in lung deflation compliance or area of pressure-volume loop hysteresis between groups before expsoure to O2. Exposure to OAP caused significant increases in lung weights and lung weight/body weight ratios by 48 h in all groups. Lung dry/wet weight ratios decreased in all groups initially but returned to non-OAP levels at 72 h. Lung compliance had decreased significantly from non-OAP levels 56 h in the normal (p equals 0.018), AY-9944 (p equals 0.045) and hydrocortisone (p equals 0.002) groups and after 72 h in the saline group (p equals 0.0015). AY-9944-treated rats had the highest mortality rate from OAP. By 72 h OAP, 40.0% of the normal, 42.9% of the hydrocortisone, 50.0% of the saline, and 100% of the AY-9944 animals were dead. Our study suggests that the effect of AY-9944 on lung lipid metabolism is more detrimental in OAP-exposed rats than the expected benefit of AY-9944's simultaneous reduction in adrenal cortical activity.