Background Epidermolysis bullosa is a group of inherited skin fragility diseases varying in severity from mild scarring to infant mortality. Great efforts are being undertaken to develop therapeutic strategies to treat the more pernicious forms of this disease, particularly those associated with recessive, loss-of-function mutations. In such cases significant effort is directed toward delivering recombinant protein at levels sufficient to demonstrate clinical benefit. Recessive dystrophic epidermolysis bullosa (RDEB) predisposes patients to a high incidence of life-threatening cutaneous squamous cell carcinoma (cSCC). Mutations in the gene encoding type VII collagen, COL7A1, are the sole cause of this disease and conflicting reports concerning type VII collagen and COL7A1 in carcinogenesis exist. Objectives To investigate potential oncogenic effects of expressing recombinant type VII collagen in patient cells. Methods We used retroviral transduction to introduce type VII collagen into keratinocytes derived from patients with and without RDEB. Results Retroviral expression of type VII collagen in cSCC keratinocytes established from patients with RDEB resulted in increased cell adhesion, migration and invasion coupled with a concurrent increase in PI3K and MAPK signalling. Conclusions Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer. What's already known about this topic? Recombinant type VII collagen induces invasion of recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes transformed with oncogenic Ras and IκBαM via activation of the PI3K pathway. What does this study add? High levels of type VII collagen expression induce increased migration and invasion in RDEB cutaneous squamous cell carcinoma keratinocytes and a concurrent increase in activation of the PI3K pathway. Therapeutic efforts to restore type VII collagen expression in patients with RDEB should be mindful of increasing protein levels above endogenous levels. © 2013 British Association of Dermatologists.