The metabolism of ethanol and its oxidation product, acetaldehyde, was studied in Japanese volunteers. Subjects who responded by facial flushing and tachycardia were found to accumulate acetaldehyde during ethanol intoxication, in contrast to the near absence of blood acetaldehyde in nonflushing subjects. There were large individual variations in acetaldehyde accumulation observed in the former group, and this accumulation correlated well with the intensity of the physiological responses, but not with rate of ethanol elimination. Oral pretreatment with the alcohol dehydrogenase inhibitor, 4-methylpyrazole, reduced ethanol elimination by 15-25% and strongly suppressed acetaldehyde accumulation. However, here too there was no relation between individual ethanol elimination rate and acetaldehyde accumulation. Furthermore, the change in the blood lactate/pyruvate concentration ratio after ethanol intake was apparently unrelated to the degree of acetaldehyde accumulation. These results, combined with our previous observation of a strong negative correlation between increase in heart rate and activity of cytosolic aldehyde dehydrogenase in erythrocytes, suggest that in flushing Orientals lacking the low-Km aldehyde dehydrogenase isozyme, the alternative cytosolic enzyme is responsible for acetaldehyde oxidation, and its activity probably determines the individual variation of acetaldehyde-mediated physiological responses.