Abstract Introduction Vascularised composite allotransplantation (VCA) permits like-for-like reconstruction following extensive soft tissue injuries. The initial management of extensive soft tissue injury can lead to the development of anti-HLA antibodies through injury, transfusion and cadaveric grafting. The role of antibody-mediated rejection, donor-specific antibodies and graft rejection in the context of VCA remains unclear. This systematic review aimed to determine whether pre-operative management strategies influence immunological outcome following VCA. Method A systematic review of MEDLINE, EMBASE and CINAHL using a PRISMA-compliant methodology up to February 2019 was conducted. Pre-operative, procedural and long-term outcome data were collected and recorded for all VCA recipients on an individual patient basis. Result The search revealed 3,847 records of which 114 met inclusion criteria and reported clinical data related to 100 patients who underwent 129 VCA transplants. Trauma (50%) and burns (15%) were the most frequent indications for VCA. Of all 114 studies, only one reported acute resuscitative management. Fifteen patients (14.7%) were sensitized prior to reconstructive transplantation with an 80% incidence of acute rejection in the first post-operative year. Seven patients demonstrated graft vasculopathy, only one of whom had demonstrated panel reactive antibodies. Conclusion Currently employed acute management strategies predispose to the development of anti-HLA antibodies, adding to the already complex immunological challenge of VCA. Early appropriate care is warranted in patients with extensive soft tissue loss where the resuscitative needs should be balanced against strategies to mitigate the immunological burden, particularly as reconstructive transplantation becomes a feasible option for future soft tissue coverage. Take-home message Acute resuscitative management may sensitise potential transplant recipients following major soft tissue injury. Early appropriate care is warranted.