Thirty-three consecutive liver-transplant recipients were prospectively studied over a 37-mo period for evidence of cytomegalovirus infection. Sixteen (48%) episodes of cytomegalovirus infection were identified; 9 were primary infections and 7 were recurrent infections. Beginning with patient 8, gamma-globulin prophylaxis was routinely administered to most patients. Twelve potential risk factors for cytomegalovirus infection were evaluated and included pretransplant cytomegalovirus serological status of donor and recipient; recipient's age, sex, race, and liver disease; number and type of blood products transfused; type and intensity of immunosuppression; and occurrence of rejection. The Cox proportional hazards model identified positive donor cytomegalovirus serology as the single most important risk factor for subsequent development of cytomegalovirus infection, regardless of recipient cytomegalovirus serological status. In addition, use of gamma-globulin prophylaxis seemed to be protective against the occurrence of disseminated cytomegalovirus disease.