Medical devices, such as non-invasive ventilation masks, save lives in health care settings but can be a cause of tissue injuries due to the pressure and shear loads on skin and soft tissue. These pressure injuries could be painful for the individual and cause a significant economic impact on healthcare providers. In the etiology of device related pressure ulcers, inflammation plays an important role. However, the exact nature and timing of inflammatory biomarker upregulation is still unknown in the early stages of skin damage. This study aimed to explore the inflammatory profile of vulnerable skin sites following non-invasive mask application on a convenience sample of eleven hospital patients. Seventy-one inflammatory proteins were explored from sebum sampled at the skin surface after oronasal mask application. A multivariate analysis to investigate differences between loaded and control site was conducted, with a protein network analysis used to explore interactions in the early inflammation. The study revealed that 21 cytokines and chemokines were important for the separation between loaded and control site. These proteins were associated with remodeling of tissue, vascular wound healing and/or cell death.