Infection of the rhesus macaque (Macaca mulatta) with simian immunodeficiency virus (SIV) induces a disease similar to AIDS. We compared SIV-specific antibody and antigenemia with the progression of disease in monkeys experimentally infected with SIV/Delta isolates that varied in pathogenicity. Western blot, immunoprecipitation, and sandwich enzyme-linked immunosorbent assay of serial sera from macaques infected with attenuated virus revealed a persistent antibody response and no evidence of SIV antigenemia. Immunosuppressed macaques without central nervous system (CNS) infections responded similarly to initial infection, but antibody specific for gag or, less frequently, to gag and env determinants declined predictably before clinical disease. Monkeys with CNS infections, however, had little, if any, detectable antibody to either envelope or gag proteins, regardless of the duration of survival. SIV/Delta-specific antigenemia, evident only in immunodeficient monkeys, fluctuated reciprocally with antibody. Our data suggest that SIV/Delta-induced disease is dependent upon antigenemic episodes that, particularly in animals with CNS infection, appear coincident with diminished antibody.