Because male and female livers not only differ with respect to estrogen and androgen receptor content, but also demonstrate sexual dimorphism of certain functions, we examined the effect of donor gender on graft survival following liver transplantation (OLTx) in adults. Between February 1981 and February 1988, 982 OLTx procedures were performed in 789 adult patients at the University of Pittsburgh. In this study, OLTx was categorized as a failure if the patient died or required retransplantation within 60 days of the surgery. When the donor-recipient gender combinations were male-male, male-female, and female-female, the failure rates were 28%, 28%, and 36%, respectively. In contrast, 60% of female donor livers failed in male recipients. Compared to the pooled donor-recipient gender combinations, the odds of failure for female-male liver grafts were increased 3.7-fold (95% confidence interval: 6.5, 2.1; P < 0.001). These findings may result, at least in part, from alterations in the sex hormone milieu or changes in the graft estrogen or androgen receptor content.