The effect of short-term administration of chlorpromazine and phenobarbital on cytoplasmic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) was studied in distinct brain regions of the male rat. The effect of exposure to cold environment on the same enzymes was also evaluated. Chlorpromazine treatment resulted in inhibition of ADH and ALDH in the striatum and in the cerebellum, respectively. This inhibition was determined only when the animals were sacrificed 30 min but not 18 hr post terminal drug treatment. The pons-medulla content of ALDH was reduced by chlorpromazine treatment from controls 18 hr of terminal treatment. Hypothermic animals showed an inhibition of ADH in the diencephalon from corresponding controls. The phenobarbital treatment was devoid of action on hepatic ADH and ALDH. Concomitantly, an induction of both ADH and ALDH by pentobarbital was observed in the cerebellum and in the diencephalon, respectively. The effect of the drugs studied may contribute to their adverse interaction with ethanol on the central nervous system.