Excessive UVR ranks among the most harmful environmental influences on human skin. However, the direct impact of UVR on human skin appendages remains to be systematically investigated. Organ-cultured human anagen hair follicles in vitro were irradiated, and reduction of hair shaft elongation, premature catagen entry, and reduced hair matrix keratinocyte proliferation were observed upon irradiation with UVB (20/50 mJ cm 2). At 20 mJ cm 2, apoptotic cell death prevailed (casp-3/p53 activation), whereas at 50 mJ cm 2, necrotic cell death was predominant (lactate dehydrogenase increase). Mitochondrial common deletion and oxidatively damaged genomic DNA (8-OH-dG) was mainly observed at 20 mJ cm 2. Follicular melanogenesis and ACTH immunoreactivity drastically declined, but α-melanocyte-stimulating hormone remained unchanged, whereas transforming growth factor-Β 2 expression shifted from the outer toward the inner root sheath. Both the number of Giemsa mast cells and the degree of mast-cell degranulation increased in the connective tissue sheath (CTS), and CD117 immunoreactivity of CTS cells and matrix keratinocytes was upregulated. Thus, UVR differentially modifies hair growth and cycle, promotes cell death, and induces complex regulatory events in human hair follicles in vitro. The leads from this human organ model, which is a living and human tissue interaction system under physiologically relevant in situ conditions, may encourage its use for general investigation of UV-induced effects as well as for testing possible agents for their UV-protective potency. © 2009 The Society for Investigative Dermatology.