The role of the cytotoxic crossmatch in liver transplantation is generally considered controversial. The development of the flow cytometric crossmatch has allowed the detection of lower levels of donor-directed IgG than is possible with the conventional crossmatch. This assay has been shown to be useful in renal transplantation. However, with the controversial role of the standard cytotoxic crossmatch, the flow cytometric crossmatch has not been used in liver transplantation. Twenty-seven human orthotopic liver allograft recipients were tested for donor-directed IgG using the flow cytometric crossmatch. Thirteen recipients were identified with either T or B lymphocyte-directed IgG. This group had a significantly increased incidence of clinical rejection (75%) as compared with the negative group (29%, P = 0.02, Fisher's exact test). The differences were greatest with B lymphocyte-directed IgG and the rejections were generally steroid sensitive. In this series, the flow cytometric crossmatch proved to be a better prognostic indicator of rejection than the conventional cytotoxic crossmatch. In addition, the association of a positive flow cytometric crossmatch with rejection indicates that the liver follows the same pattern seen in renal and cardiac grafts.