Pressure ulcers (PU) are caused by the interplay of multiple factors including skin microcirculation. Ischemia-reperfusion (I/R) injury is considered a significant mechanism in the early stages of pressure ulcer development. The objective of this controlled, single-blinded in vivo study was to create a pressure-induced injury rat animal model and explore the possible mechanism and effects of I/R injury in early stage PU development using clinically relevant amounts of pressure and pressure duration. Forty-eight animals were randomly divided into six groups of eight and a 2.5 cmx2.5 cm area of the hip was subjected to no pressure (control), ischemia only (IG--2 hours of 70 mm Hg pressure), or one of four I/R cycles (70 mm HG of pressure for 2 hours followed by 1, 2, 3, or 4 hours of reperfusion). All I/R cycles were repeated three times. Full-thickness skin samples from the compressed area were harvested for histopathology and femoral artery blood samples obtained to measure serum levels of the following inflammatory mediators: malondialdehyde (MDA), superoxide dismutase (SOD) nitric oxide (NO) and endothelin-1 (ET-1). MDA, NO, and ET-1 levels were significantly higher in the IR than the control (P<0.01) and ischemia groups (P<0.05); whereas, SOD activity was significantly lower than in the IG and control groups (P<0.05). The largest differences were observed in the 2-hour ischemia/3-hour reperfusion group. Biopsy analysis by lightmicroscopy stain showed no changes in the control, mild changes in the IG, and considerable damage, including leukocyte infiltration, collagen fibrosis, and edema in epidermal, dermal, and muscle tissue from the I/R group. These findings suggest that hypoxic-ischemic tissue injury occurs early following a period of ischemia and that I/R may be an important mechanism in PU development. Although the mechanisms of I/R injury are probably multifactorial and the actions of free radicals may be more complicated in the early stages of PU development in humans, the findings suggest that a minimum of 4 hours pressure relief may be helpful for PU prevention. Research to elucidate these mechanisms and their potential interactive effects to help clinicians develop evidence-based prevention protocols are warranted.