Multiple lines of clinical and experimental evidence suggest that human herpesvirus 6 (HHV-6) may act as an accelerating factor in the natural history of human immunodeficiency virus (HIV) infection. Although, in common with HIV, HHV-6 has a primary tropism for CD4+ T cells, its potential effects on the immune system are broader. For instance, HHV-6 can also infect and kill CD8+ T cells, natural killer cells and mononuclear phagocytes. Here, Paolo Lusso and Robert Gallo suggest that understanding the immunopathogenic role of HHV-6 in the course of HIV infection may shed new light on the complex mechanisms of disease progression in AIDS.