The risk/benefit ratio of face trasnplant is still a matter of debate that could be solved with a clinical resarch protocol looking at reproducibility, difficulties, serious adverse events and outcomes in terms of quality of life. Patients and Methods Five patients were included in a registered clinical research protocol after a thorough clinical and biological screening, as assessed by an independent expert committee. Origin of defiguration were one bilateral plexiform neurofibromas, two extensive third degree burns and two gunshot injuries. Face transplants were harvested from heart-beating, brain-dead donors. The induction immunosuppressive regimens included anti-thymocyte globulins, steroids, mycophenolate mofetil and tacrolimus; the maintenance therapy included these last three components. Extracorporeal photopheresis was used as an adjuvant immunomodulatory therapy. Results Four patients were transplanted with a maximum follow-up of 36 months and a minimum of 6 months. One patient who was on the waiting list for 18 months could not be transplanted due to his panel of reactive antibodies. Three patients experienced biopsy-proven acute cellular rejection episodes that were easily controlled by conventional treatment. Voluntary facial activity appeared after 3 to 5 months. All patient experienced various infections that could have been life threatening. These infections were either local or general. One of our patients died two months after transplantation due to a multi-resistant bacterial infection. The dramatic changes obtained in the facial aesthetic and function and the improvement in patients' quality of life were of the same extent. Conclusion Face transplantations are feasible and reproducible, and they have allowed major improvements in the quality of life of patients however life threatening infections are a majot pitfall. Face transplant represents a change in the paradigm of facial reconstruction as well as of transplantation that might lead society to accept these new types of harvested organs and tissues.