Background: Epidermolysis bullosa simplex (EBS) is the most common type of EB, accounting for 70% of cases. Mutations in keratin 5 and keratin 14 genes are responsible for the four major types of EBS. The susceptibility of keratinocytes to caspase-8-mediated apoptosis is suggested to be increased in mutated K14 keratinocytes.Aim of the work: The current study aims at studying the expression of caspase 8 in lesional and non-lesional skin of EBS patients in comparison to normal control skin in order to highlight the possible role of apoptotic/inflammatory pathways in the pathogenesis of this disease.Subjects and methods: This cross sectional case control study was conducted on 10 patients proved to have EBS by electron microscopic examination. They underwent two 4 mm punch biopsies; one from a fresh blister and the other from non-lesional skin, for histopathological assessment of the density of dermal infiltrate and for immunohistochemical detection of caspase 8. Five age and sex matched healthy volunteers served as controls. Results: Caspase 8 expression both in lesional and non-lesional skin was significantly higher than in controls (p<0.01 and p=0.013 respectively). No significant difference existed as regards caspase 8 expression between lesional and non-lesional skin (p=1). The density of dermal infiltrate was significantly higher in lesional skin (p=0.02). A strong significant positive correlation was found when correlating caspase 8 expression in lesional skin with the extent of the disease, the rate of blistering, and the density of dermal infiltrate (r=0.835, p=0.003, r=0.889, p=0.001and r= 0.776, p=0.008 respectively). Conclusion: Keratin mutation is only a conductor of an orchestra of events in the pathogenesis of EBS. Caspase-8-mediated apoptosis is an integral component of this orchestra. We propose the term apo-cytolysis to better describe the exact mechanism of blistering in EBS. Inflammation is secondary to apo-cytolysis.