ObjectiveElectrical epilation of unwanted hair is a widely used hair removal method, but it is largely unknown how this affects the biology of human hair follicles (HF) and perifollicular skin. Here, we have begun to explore how mechanical epilation changes selected key biological read‐out parameters ex vivo within and around the pilosebaceous unit.MethodsHuman full‐thickness scalp skin samples were epilated ex vivo using an electro‐mechanical device, organ‐cultured for up to 6 days in serum‐free, supplemented medium, and assessed at different time points by quantitative (immuno‐)histomorphometry for selected relevant read‐out parameters in epilated and sham‐epilated control samples.ResultsEpilation removed most of the hair shafts, often together with fragments of the outer and inner root sheath and hair matrix. This was associated with persistent focal thinning of the HF basal membrane, decreased melanin content of the residual HF epithelium, and increased HF keratinocyte apoptosis, including in the bulge, yet without affecting the number of cytokeratin 15+ HF epithelial stem cells. Sebocyte apoptosis in the peripheral zone was increased, albeit without visibly altering sebum production. Epilation transiently perturbed HF immune privilege, and increased the expression of ICAM‐1 in the bulge and bulb mesenchyme, and the number of perifollicular MHC class II+ cells as well as mast cells around the distal epithelium and promoted mast cell degranulation around the suprabulbar and bulbar area. Moreover, compared to controls, several key players of neurogenic skin inflammation, itch, and/or thermosensation (TRPV1, TRPA1, NGF, and NKR1) were differentially expressed in post‐epilation skin.ConclusionThese data generated in denervated, organ‐cultured human scalp skin demonstrate that epilation‐induced mechanical HF trauma elicits surprisingly complex biological responses. These may contribute to the delayed re‐growth of thinner and lighter hair shafts post‐epilation and temporary post‐epilation discomfort. Our findings also provide pointers regarding the development of topically applicable agents that minimize undesirable sequelae of epilation.