Acute graft-versus-host disease (GvHD) is an uncommon but often fatal complication after orthotopic liver transplantation (OLT). To determine whether there is an association between human leukocyte antigen (HLA) matching and the development of GvHD after cadaveric OLT, we undertook a retrospective, single-center analysis of 412 consecutive adult recipients where HLA typing data was available. Seven (1.7%) recipients developed acute GvHD, and six died from their disease. Donor compatibility at HLA-B but not at HLA-A or -DR was identified as a significant risk factor for the development of GvHD. Of 14 recipients with no HLA-B mismatches, 3 (21%) developed GvHD (odds ratio 27, P<0.001). Conversely, of 262 recipients mismatched at both HLA-B loci, only 1 (0.4%) developed GvHD (odds ratio 0.09, P<0.01). Our findings suggest that patients receiving a liver allograft with no HLA-B mismatched antigens are at increased risk of developing GvHD.