Complications after lung transplantation include the development of rejection and an increased incidence of infection, particularly with cytomegalovirus (CMV). Several recent studies have suggested that interleukin (IL)-6 may be used to detect both infection and rejection after lung transplantation. In addition, IL-6 may play a role in the development of bronchiolitis obliterans after transplantation. Because CMV is also associated with the development of bronchiolitis obliterans after transplantation, we determined whether CMV induces IL-6 gene expression. We demonstrated that CMV infection increased both IL-6 protein and mRNA in peripheral blood mononuclear cells. We also demonstrated that the CMV immediate early 1 gene product increased expression of the IL-6 promoter. This effect of the CMV immediate early 1 gene product was dependent upon the presence of specific transcription factor binding sites in the IL-6 promoter. These studies demonstrate that CMV may be an important cofactor in the development of rejection and infection after transplantation through its effects on IL-6.