The pathophysiology of cold injury is still controversial. An inflammatory process has been implicated as the underlying mechanism and certain anti-inflammatory substances such as ibuprofen and acetylsalicylic acid have been used in the clinical treatment of frostbite injury. It has been postulated that the progressive ischemic necrosis is secondary to excessive thromboxane A(2) production, which upsets the normal balance between prostacyclin (prostaglandin Ig) and thromboxane A(2). It was aimed to clarify the pathophysiology of cold injury in this study. Twenty-one New Zealand White rabbits, each weighing 1.2 to 2.9 kg, were divided into control (n = 10) and frost bitten (n = 11) groups the randomly. The rabbit ears in the frostbitten group were subjected to cold injury, and the levels of thromboxane A(2) (as thromboxane B-2) and of prostaglandin I-2 (as 6-keto-prostaglandin F-1 alpha) and the number of inflammatory cells (polymorphonuclear leukocytes and mast cells) were measured in normal and frostbitten skin of rabbit ears. The levels of 6-keto prostaglandin F-1 alpha and thromboxane B-2, the stable metabolites of prostaglandin I-2 and thromboxane A(2), respectively, were increased in a statistically significant way (p < 0.002) by frostbite injury; however, thromboxane B-2 increased more than 6-keto prostaglandin F-1 alpha. Polymorphonuclear leukocytes and mast cells, absent in normal skin, were present in the frostbitten skin. There was a statistically significant (p < 0.01) correlation between the time a rabbit ear was maintained at below -10 degrees C and skin survival and between the weights of rabbits and skin survival (p < 0.024). All these findings suggest that inflammation is involved in frostbite injury; a decrease in prostaglandin I-2/thromboxane A(2) ratio could be one of the factors leading to necrosis; the bigger the animal, the better its ability to counter frostbite.