In previous studies cytomegalovirus (CMV) infection was identified as one risk factor in the development of vanishing bile duct syndrome (VBDS) after orthotopic liver transplantation (OLT), but its precise role in relation to the pathogenesis of tissue damage is uncertain. In the present study a-interferon (α-IFN) expression in the liver was studied as an indirect marker of viral infection in serial liver biopsies from 42 patients following OLT. α-IFN was identified more frequently in the bile duct cytoplasm of patients developing VBDS, with or without evidence of preceding CMV infection (7/8 and 4/5 cases, respectively), when compared with patients with acute CMV but without evidence of VBDS (6/19 cases; P<0.05) or those with neither complication (2/10 cases; P<0.01). α-IFN was detectable in bile duct cytoplasm for a longer period in patients developing VBDS than in those with acute CMV infection alone (median 14 weeks and range 9–19, median 6 weeks and range 1–11 weeks, respectively; P< 0.025). These data indicate that persistent CMV infection of bile duct cells is a likely co-factor linked to progression to VBDS, but the processes that allow persistent viral infection and bile duct destruction remain to be determined.