Epidermolysis Bullosa (EB) is a group of inherited blistering disorders potentially life-threatening to newborns and infants. Stratified squamous epithelium is highly altered. Predominantly, it affects skin and mucous membrane. The unifying diagnostic feature is the extreme fragility of the skin. There is a wide phenotypic variability from very mild to extremely severe manifestations [1]. Genetically, different types of EB have different inheritance patterns [2]. Furthermore, there exists genetic heterogeneity and 13 different genes have been associated with these blistering conditions [3]. Recessive Dystrophic EB Inversa (RDEB-I) (OMIM: #226600) is a subtype of RDEB with a very low prevalence (prevalence estimated of DEB is 0.4–0.6 per million live births [4]). It is caused by mutations in the COL7A1 gene situated on chromosome 3p21.1, coding for the chain α-1 of Collagen VII. It is a 350 kDa polypeptide with a distinct structural domain organization and is the predominant component of the anchoring fibrils at the dermal-epidermal junction [5]. COL7A1 is a complex gene, consisting of 118 exons and approximately 32 kb. RDEB mutations include nonsense, splice site, deletions or insertions, silent glycine substitutions and non-glycine missense mutations [6]. Very few cases of RDEB-I have been reported to date and about 29 genotypes have been recorded [7, 8]. RDEB-I is characterized by blistering from birth and early infancy. Later in infancy, blisters localisation change to body flexures, axis and mucous membranes [2]. Patients suffer healing with scarring and skin atrophy, oral, oesophageal, genital mucosal involvement, dental caries and variable nail dystrophy and presence or absence or milia. From the reproductive point of view, if mutation/s is/are identified, prenatal diagnosis (PND) and genetic counselling is available for subsequent pregnancies. Nowadays, preimplantation genetic diagnosis (PGD) represents an alternative to PND. PGD was developed in the nineties [9] for couples at high risk of transmitting a genetic disease. Currently, PGD is available for a large number of genetic disorders [10] and the number of cases increases year by year [11]. Briefly, PGD consists on a very early form of genetic diagnosis performed in preimplantation human embryos obtained after in vitro fertilization (IVF) treatments. Using micromanipulation technology, one or two cells are biopsied from embryos at the 6 to 8 cell stage. The single embryonic cells (blastomeres) are analysed individually by polymerase chain reaction (PCR). At this stage, the embryonic cells are totipotent and undifferentiated and the genetic status of the blastomere can be extrapolated to the complete embryo. The biopsied embryos are incubated for 24 to 48 h, awaiting the genetic diagnosis results. Finally, healthy embryos are transferred into the maternal uterus. In cases of PGD for single-gene disorders, the first premise is to have an accurate genetic diagnosis of the candidate couple. Dermatologically, more than 70 disorders are hereditary. In many cases, the genetic diagnosis is complex, time-consuming and costly. In this paper we aim to present the design of the first ad hoc-PGD protocol applied clinically in a couple with a previous affected child of RDEB-I. The novelty of this case consists on the description of the complete process: accurate genetic diagnosis of the affected child, mutation detection in the parents, pre-clinical informativity study, single-cell validation studies, and pregnancy after clinical PGD. Unfortunately, at the time of writing this manuscript, a miscarriage was reported by obstetric problems at 15 weeks of gestation.