Currently, pressure ulcer preventive strategies focus mainly on pressure redistribution. Little attention is paid to reduce the harmful effects of shear-force, because little is known about pathophysiological aspects of shear-force. Even today, no method to measure the effects of shear-force on the skin is available. Therefore, the aim of this study was to investigate the response to shear-forces in terms of analyzing a noninvasive biomarker and reactive hyperemic parameter measured at the skin of healthy participants. A physical model was developed to produce a combination of pressure and shear or pressure alone on the skin. Ten healthy male participants were included and pressure (3.9 kPa) and a combined loading of pressure and shear (2.4 kPa + 14.5 N) was applied at the volar aspect of the forearms for 15 and 30 minutes. A Sebutape sample was used to collect IL-1α and total protein (TP) noninvasively. The reactive hyperemic parameter was derived from a laser Doppler flowmeter. The increase in IL-1α/TP-ratio after a combined loading of pressure and shear for 30 minutes of 6.2 ± 2.5 was significantly higher compared with all other test conditions (p < 0.05). The increase in cutaneous blood cell flux was already significantly higher when a combined loading of pressure and shear was applied for 15 minutes compared with pressure alone. These results shows that the IL-1α/TP-ratio and cutaneous blood cell flux can be used as robust measures of the effect of shear-force on skin in humans. Therefore, this model can be used to evaluate materials aimed at the reduction of shear.