The incidence of cytomegalovirus (CMV) disease, once the most common and highly feared viral complication of AIDS, has dramatically decreased with the advent of highly active antiretroviral therapy (HAART). HAART-associated changes in the epidemiology of CMV disease resulted from the increase in CMV-specific immune responses coupled with the decrease in CMV reactivation. However, CMV disease continues to afflict HIV-infected patients on HAART when CD4+ cell counts fail to rise above 100 cells/mm(3) and when reconstitution of normal CMV-specific immune responses does not occur. The latter scenario may lead to recurrent or de novo CMV end-organ disease, or to the recently described CMV immune recovery vitritis. HAART-associated immune reconstitution offers unique opportunities to investigate the virological and immunological correlates of protection against CMV disease. Although the full extent of CMV-specific immune reconstitution has not been defined thus far, CMV-specific interferon-gamma production has been shown to be significantly associated with protection against CMV reactivation and recurrent disease.