The contribution of cytomegalovirus (CMV) infection and its interrelation with HLA antigens in the development of chronic rejection (vanishing bile-duct syndrome--VBDS) was investigated in 101 patients surviving for at least 3 months after liver transplantation. A 1-2 antigen match for HLA DR antigens (30.9% vs 4.5% for zero DR match; p less than 0.002), a zero match for HLA A/B antigens (27.5% vs 10.9% for 1 or more A/B match; p less than 0.05), and active CMV infection (26.3% vs 4.4% for no CMV infection; p less than 0.005) were independently associated with an increased risk of VBDS. The coexistence of a 1-2 HLA DR match and CMV infection carried the highest relative risk (10.1) of VBDS; these two variables were probably interdependent since either alone was associated with a low relative risk (0.45 and 0.5). The association between VBDS and active CMV infection was not a consequence of alterations in immunosuppressive therapy. The findings would be consistent with precipitation of chronic rejection by CMV-induced HLA antigen expression in patients rendered susceptible by the donor/recipient HLA antigen match.