Abstract: Acute rejection (AR) of human hand allografts (HHAs) may carry a risk of graft loss and leads to the need for immunosuppressive treatment. The literature on HHAs was reviewed to determine and evaluate the factors that trigger AR of HHAs. Clinical case reports of hand allograft transplantation published between 1999 and 2011 in English, French, or German were reviewed systematically. The number of AR episodes was the main outcome measure. Sixty-eight episodes of AR were described in 28 recipients. Calcineurin inhibitor-based maintenance regimens were associated with significantly fewer AR episodes than non–calcineurin inhibitor-based regimens (mean 1.9 vs 3.2; P = 0.018). In recipients who experienced cytomegalovirus infection, the mean number of episodes of AR was 4, whereas in those who did not experience cytomegalovirus infection it was 2.25 (P = 0.024). The planning of hand allograft transplantation should take these factors into account to minimize the risk of AR.