To elucidate further the reproductive effects of human leukocyte antigen (HLA) sharing among spouses, we have been investigating prospectively the relationship between HLA-A, -B, and -DR sharing and reproductive outcome in the Hutterites, a religious isolate that proscribes contraception. For the first time the reproductive effects of HLA-DR sharing in a fertile population is reported in this article. Median intervals from marriage to first through fifth births were longer among couples who shared more than one HLA-A, -B, or -DR antigen. Longer intervals were associated with increased spontaneous abortion rates among couples who shared HLA-DR antigens (27%), compared with couples who shared only HLA-A, or -B antigens (9%) and couples who shared no antigens (12%). Median completed family sizes were 5.0, 8.5, and 8.0 among the groups, respectively. However, some couples who shared HLA-DR antigens experienced no spontaneous abortions, despite ten or more pregnancies. Therefore, although HLA-DR compatibility, per se, is not deleterious, our data suggest a potentially important role for undefined HLA-linked genes in normal pregnancy.