Cytomegalovirus (CMV) infects most individuals and elicits a strong CMV-specific immune response. We have studied the influence of CMV-seropositivity on the size of lymphoid subsets in healthy donors and demonstrate that the virus substantially modulates the peripheral lymphoid pool. CD8+ T cell numbers are increased in all CMV-seropositive individuals because of a striking 60% increment in the CD8+ T cell memory pool. The CD45RA+ resting memory pool is doubled after CMV infection and increases further with age. The magnitude of the naïve CD8+ T cell pool is dramatically reduced in CMV-seropositive individuals at all ages, and this accelerates the physiological decline by approximately 40 years. The number of CD4+ effector memory T cells is increased in CMV-seropositive individuals and is differentially accommodated by a reduction in the number of naïve and central memory CD4+ T cells in young and elderly donors respectively. CMV-seropositivity also increases the total number of B cells in older donors and suppresses the number of CD5+ B cells. These data reveal that CMV has a profound influence on the immune system of all healthy individuals and add to growing concern regarding the clinical and immunomodulatory significance of CMV infection in healthy donors.