Pressure ulcers are generally associated with external pressures exceeding internal capillary pressures over bony prominences when the body cannot initiate motor movement to change positions. This investigation evaluated microstructural changes occurring in human skin, in vitro, exposed to static versus cyclic pressures, simulating those recorded for heels of human subjects on various pressure-relief mattresses. Morphological data are reported for tissues exposed to pressure in a bench-scale loading system. Dynamic (cyclic-relief) pressure induced parallel alignments of connective tissue collagen bundles, which themselves became differentially oriented to various degrees perpendicular to the surface of the tissue. Static pressure, with no relief, invariably produced alignment of the collagen bundles of the connective tissue parallel to both one another and to the compressed tissue surface. The precursor to pressure ulcer formation may be microstructural alignment in response to the pressure conditions on tissue.