Purpose: The results of laboratory animal studies indicate that pretreatment with prostaglandin synthesis inhibitors (PGSIs) reduce the pharmacologic and toxic effects of ethanol. The purpose of this study was to determine if pretreatment with indomethacin, a potent PGSI, influenced the physiologic, performance and subjective effects of ethanol and pentobarbital in humans. Methods: Six residential volunteers were pretreated with indomethacin (0,12.5,25,50 and 100 mg/75 kg. Dependent measures included: physiologic (HR, blood pressure, ocular effects, oral and skin temperature), performance (cognitive tasks, card sorting, circular lights) and subjective effects (PCAG, vals, SDQ). Results: Ethanol and pentobarbital (300 mg) caused similar degrees of performance impairment and subjective effects. Indomethacin did not change the BAL after the ethanol which averaged 120 mg%. Indomethacin pretreatment exaggerated the subjective response to low doses of pentobarbital and diminished ethanol-induced cognitive impairment. Significance: The importance of this research lies in the understanding of the role of prostaglandin in mediating the psychotropic effects of ethanol and pentobarbital in humans. Although animal studies indicate these processes are involved in some central effects, prostaglandin release evidently does not play a large role in the effects of ethanol in humans. The research, however, provides a model test in humans to investigate other compounds for their ability to antagonize the effects of ethanol and pentobarbital.