It has been suggested that cofactors in human immunodeficiency virus (HIV) disease, particularly other viral infections, may accelerate progression to the acquired immune deficiency syndrome (AIDS). We have shown that in a population of 108 HIV-infected hemophiliacs observed for up to 9 years after the first documented HIV seroconversion, coinfection with cytomegalovirus (CMV) adversely influenced the course of the disease; in particular, logistic regression analysis showed that the age-adjusted relative risk of developing AIDS in CMV-seropositive patients was 2.5 times that in CMV seronegatives (p = 0.02). A number of potential mechanisms for the interaction of HIV and CMV have been proposed. Several groups have reported interaction at a molecular level between HIV and other viruses, including CMV, through transactivation of the HIV genome. Mechanisms by which the two viruses might gain entry to the same cell have been identified in vitro; these include Fc receptor-mediated uptake of antibody-coated HIV by CMV-infected fibroblasts. There is also some evidence that coinfection with HIV and CMV can occur in vivo, within brain cells. Interaction between these two viruses might also occur indirectly through the production of cytokines, such as tumor necrosis factor. Identification of cofactors in HIV infection may help in understanding the pathogenesis of AIDS, and may provide an important opportunity for intervention in the progression of the disease, particularly when an infectious agent for which specific therapy is available is identified.