Intermittent negative pressure devices were initially developed by NASA to enhance blood perfusion and combat a reduction in orthostatic tolerance. Investigational studies have demonstrated that the pressure differential produces changes in the blood and cardiac systems and also documented changes in weight and cellulite in obese patients. Although the mechanisms are not known, previous investigation has also reported changes in lymphedematous limbs. These initial results suggested to us that the inclusion of intermittent negative pressure into a lymphedema treatment protocol would be beneficial. We subsequently undertook a study of 50 patients with lymphedema adding intermittent negative pressure to our CLyFT protocol and compared them to the CLyFT protocol without intermittent negative pressure. We found a significant difference between the groups with an additional 7% reduction in lymphedema volume (p = 0.008). Our study results indicate that the inclusion of intermittent negative pressure therapy into the CLyFT protocol was beneficial and further incorporation into other protocols should be investigated.