Negative pressure wound therapy (NPWT) alters wound edge microvascular blood flow. Some preclinical data suggest that cycling between low and high negative pressure may be more beneficial than continuous NPWT. The purpose of this in vivo study was to compare the effect of intermittent negative pressure (cycled either from 0 to -75 or to -125 mm Hg) and variable negative pressure (cycled from -10 to -75 or -125 mm Hg or from -45 to -75 or -125 mm Hg) on wound edge microvascular blood flow. Using a peripheral wound model (n = 8 domestic 70-kg pigs), intermittent and variable NPWT was applied to surgically created wounds (5 cm diameter, 2 cm depth) for five cycles of 5 minutes of high and 2 minutes of low pressure. Blood flow was measured using laser Doppler velocimetry in subcutaneous and muscle tissue at 0.5 and 2.5 cm from the wound edge. When NPWT was applied, blood flow decreased an average of 29% +/- 2% in muscle tissue and 22 % +/- 4% in subcutaneous tissue at -75 mm Hg at 0.5 cm from the wound edge and increased an average of 20% +/- 6% for -75 mm Hg at 2.5 cm from the wound edge. Blood flow changed repeatedly when negative pressure was cycled. Large gradients between the cycled pressures (eg, -10 to -75 mm Hg) resulted in greater blood flow alterations than smaller (eg, -45 to -75 mm Hg) gradients. Blood flow alternations were similar between low-pressure settings of -10 mm Hg (variable NPWT) and 0 mm Hg (intermittent NPWT) and between high-pressure settings of -75 or -125 mm Hg. Both intermittent and variable NPWT result in a beneficial combination of increased blood flow, known to facilitate oxygenation and nutrient supply, and decreased blood flow, known to stimulate angiogenesis and granulation tissue formation. Cycling the negative pressure may be especially advantageous when treating poorly vascularized tissue. In cases where intermittent therapy causes patient discomfort, variable therapy may be superior.