Pressure ulcers/injuries are caused by sustained loading and deformation of skin and underlying soft tissues. Prophylactic dressings are recommended as an adjunct to other preventive measures such as repositioning and offloading. The aim of this study was to investigate the effects of prophylactic soft silicone multi-layered foam dressings on the skin structure and function of the two most common pressure areas, sacrum and heel, with and without loading. An exploratory randomised cross-over trial using intra-individual comparisons was conducted. Eight healthy volunteers (mean age 27.5 years) were assigned to three groups and either spent 2.5 hours on a standard hospital mattress lying in supine position with and without dressings or spent 2.5 hours with dressings applied but without loading. Skin temperature, stratum corneum, and epidermal hydration increased in all groups irrespective of wearing a dressing and/or loading. Mean roughness decreased at the heels. Reactive hyperaemia and the release of interleukin 1 alpha were associated with loading only. Results suggest that the occlusive effects of dressings are similar or only slightly greater than those observed with non-loading or loading without dressings. Thus, a dressing does not cause additional irritation or skin changes during loading but it may reduce the inflammatory response.