1. 1. Thioridazine and trifluoperazine, which have been previously found in this laboratory to be the most effective calmodulin antagonists in treatment of burns, are shown here to be also effective in the treatment of frostbite. 2. 2. Electron microscopic studies have revealed a complete reversal of both the vascular and skin tissue damage induced by frostbite. 3. 3. The reversal of the vascular damage was also demonstrated by the ability of these compounds to abolish the increase in hemoglobin content in the skin. 4. 4. The reversal of the skin tissue damage was also revealed by the ability of these compounds to raise the decreased ATP level and the reduced activities of 6-phosphogluconate dehydrogenase and mitochondrial and soluble hexokinase in skin, induced by frostbite, to normal control levels.