The purpose of this follow-up study is to measure the association between corneal allograft reactions and donor-recipient HLA-A and HLA-B compatibility. Four hundred thirty-eight consecutive adult recipients of corneal grafts with known donor-recipient HLA matching were observed for allograft reactions and failures. Most of the recipients under observation (91%) were well matched for HLA-DR. Of 438 recipients, 158 (36%) completed a 3-year follow-up. Three factors were associated with endothelial allograft reactions: 2 to 4+ corneal vascularization (relative risk, 2.2; P = 0.0006), two mismatched antigens at either the HLA-A or HLA-B locus (relative risk, 2.1; P = 0.0009), and recipient wound size of 8 mm or greater (relative risk, 1.5; P = 0.05). Unexpectedly, a strong association between endothelial allograft reactions and HLA-A or HLA-B incompatibility was found in low-risk recipients defined as unvascularized recipients of a small graft (relative risk, 3.2; P = 0.004). A larger sample size is required to determine if HLA matching offers a solution for recipients with corneal vascularization.