Disease states characterized by ongoing cellular activation or antigenic stimulation, such as rheumatoid arthritis (RA), HIV-1, and organ transplant, are characterized by an increase in the number of both CD4 and CD8 T cells that have downregulated CD28 and increased the expression of the CD57 surface marker [1-6]. Studies from the transplant literature and from our own laboratories [7-9] have shown that the proportion of cells in this subset is substantially influenced by the cytomegalovirus (CMV) serostatus of the host. In HIV-1 infection the expansion of the CD8+ CD28-CD57+ phenotype has been attributed partly to the ongoing stimulation by the HIV virus itself [1, 10-12]. Given the remarkable amount of HIV antigens that are processed and presented to CD8 T cells, it would seem unlikely that CMV serostatus would play a large role in regulating this cell phenotype. However, we show here that during HIV-1 infection this phenotype is caused by CMV independently of the HIV-1 plasma RNA level or clinical status.