Toxicity of the tranquilizers, chlorpromazine and chlordiazepoxide, and the sedative hypnotics, morphine and promethazine, increased with acute exposure to cold. Toxicity of amphetamine, a stimulant, was lowered at reduced temperatures. In non-cold-acclimatized rats, all drugs tested except amphetamine produced some degree of depression in avoidance response rates. With addition of alcohol and cold, response rates were depressed further. Depressant effects of drugs, alcohol and cold appeared to be approximately additive, except in the case of chlordiazepoxide, which interacted with alcohol to produce a synergistic effect. Usually a decrease in response rate was accompanied by an increase in shock rate. Rats receiving alcohol alone, however, sometimes showed a simultaneous reduction in shock rate and response rate while amphetamine increased response rate and decreased shock rate. This stimulating effect was antagonized by both alcohol and cold. Cold-acclimatized animals responded as well or better in the cold than at room temperature despite the presence of drugs. Addition of alcohol to chlorpromazine or saline produced a depression commensurate with that observed in non-acclimatized rats. Alcohol enhanced the effects of amphetamine at reduced temperatures. There were only small differences among treatments with regard to shock rates in rats receiving saline or amphetamine. In rats given chlorpromazine, there was an increase in shock rates where responses decreased with addition of alcohol. Alcohol depressed habituated rats more than non-habituated rats. Habituated, acclimatized rats showed an even greater impairment in avoidance behavior at room temperature than did cold-acclimatized but non-habituated rats.