Based on determinations of LD50, ED50 and therapeutic index, both in mice and rats, morphine sulfate was found to be at least six times as toxic and three times as effective in the cold (4°C) as: at room temperature (22 to 24°C). In the rat, however, morphine showed a very wide margin of safety in the cold as well as at room temperature, the therapeutic index being about 180. With pentobarbital, the margin of safety as indicated by therapeutic index in mice and rats in the cold was only one-third that at room temperature, while no significant differences were noted in the ED50 (median hypnotic dose) of the drug in all species of animals tested at 4°C and at 22°C. No significant differences were found in the plasma concentrations of the test drugs at different temperatures to account for the markedly increased toxicity of morphine and pentobarbital in all animals studied, as well as the apparent increased efficacy of morphine in mice and rats acutely exposed to cold. Greater-percentage pressor response to norepinephrine was demonstrated in dogs with or without hemorrhagic hypotension at 4°C than those at 22°C. The analgesic-potentiating effect of chlorpromazine was found to be greater in rats in the cold than those at room temperature when subeffective doses of morphine were administered simultaneously with a given dose of chlorpromazine. The clinical implications of these findings are discussed and recommendations are offered.