To investigate ischemic potentiation of thermal cell killing, mammary carcinomas transplanted to the legs or tails of C3H mice were treated with hyperthermia using rubber-lined compression cuffs. During treatment, warm water was circulated through the cuffs under pressure so that blood flow to the contained tumor-bearing limbs was interrupted. Ninety min at 41.5, 42.0, or 42.5 degrees and pressures between 60 and 135 mm Hg destroyed about 50% of tumors but damaged the normal tissues. Damage increased with the degree of compression. Intermittent pressure application was therefore adopted (five 18-min periods at 80 to 90 mm Hg alternating with four periods of 5 min at zero pressure). This favored the normal tissues, a high cure rate being maintained (73%) with damage to normal tissue virtually eliminated. The most satisfactory explanation of these results is a selective heat sensitivity, augmented by ischemia, on the part of tumor blood vessels. The success of intermittent treatment is then attributable to progressive impairment of the blood supply to the tumors, preventing the heat dissipation and relief of conditions such as acidity and nutrient deficiency which would otherwise result from periodic restoration of the circulation.