The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eighty-one consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5--9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26--60, median: 59 years). There was no association between the development of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir, two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.