Animal and human lentiviruses elude host defences by establishing covert infections and eventually cause disease through cumulative losses of cells that die with activation of viral gene expression. We used polymerase chain reaction in situ double-label methods to determine how many CD4+ lymphocytes are latently infected by human immunodeficiency virus (HIV) in patient lymph nodes and whether the pool of infected cells is large enough to account for immune depletion through continual activation of viral gene expression and attrition of cells responding to antigens. We discovered an extraordinarily large number of latently infected CD4+ lymphocytes and macrophages throughout the lymphoid system from early to late stages of infection, and confirmed the extracellular association of HIV with follicular dendritic cells. Follicular dendritic cells may transmit infection to cells as they migrate through lymphoid follicles. Latently infected lymphocytes and macrophages constitute an intracellular reservoir large enough ultimately to contribute to much of the immune depletion in AIDS, and represent a difficult problem that must be resolved in developing effective treatments and protective vaccine.