Immunomodulatory effects of human beta-herpesviruses have been reported in vitro and in vivo. Clinical studies suggest that beta-herpesvirus infection may increase the risk for other infections, the severity of infection, or the tempo of disease progression. An increased incidence of bacterial and fungal infections, and graft rejection, have been reported in association with cytomegalovirus (CMV), and human herpesviruses type 6 and type 7 infections have been implicated as risk factors for CMV infection and graft rejection. Beta-herpesviruses may also interact with HIV-1 and hepatitis C. To prove a causal relationship between beta-herpesviruses and specific clinical outcomes, randomized trials, with selective suppression of the virus, are required. Such trials have been performed for CMV and showed a reduction in bacterial and fungal infections as well as rejection in selected solid organ transplant recipients. More trials are needed to evaluate whether the effects seen in observational studies are truly related.