Human immunodeficiency virus (HIV)-1 DNA and RNA levels and T lymphocyte cell surface markers were measured in blood serum and cell fractions from asymptomatic infected patients to find novel virologic and immunologic features in early disease predictive of subsequent clinical disease course. Thirty-two patients with rapid disease progression (rapid CD4+ cell loss and progression to clinical AIDS) were compared with 25 patients with stable infections (constant or rising CD4+ cell counts, no clinical disease manifestations). All HIV-1 burdens measured by polymerase chain reaction were consistently higher in specimens from rapid progressors than slow progressors. For each patient, virus burden remained relatively constant throughout the study period (mean, 42-44 months). Flow cytometry also disclosed stable lymphocyte immunophenotype patterns that correlated strongly with subsequent rapid progression to clinical disease. Thus, in early HIV-1 infection, a constellation of high virus burden and in vivo costimulatory antigen and lymphocyte activation abnormalities is predictive of rapid disease course.