BACKGROUND In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years. Studies of the histopathological, virologic, and immunologic characteristics of these persons may provide insight into the pathogenic mechanisms that lead to HIV disease and the protective mechanisms that prevent progression to overt disease. RESULTS We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease. Lymph nodes from the subjects with nonprogressive infection had significantly fewer of the hyperplastic features, and none of the involuted features, characteristic of nodes from subjects with progressive disease. Plasma levels of HIV-1 RNA and the viral burden in peripheral-blood mononuclear cells were both significantly lower in the subjects with nonprogressive infection than in those with progressive disease (P = 0.003 and P = 0.015, respectively). HIV could not be isolated from the plasma of the former, who also had significantly higher titers of neutralizing antibodies than the latter. There was viral replication, however, in the subjects with nonprogressive infection, and virus was consistently cultured from mononuclear cells from the lymph nodes. In the lymph nodes virus "trapping" varied with the degree of formation of germinal centers, and few cells expressing virus were found by in situ hybridization. HIV-specific cytotoxic activity was detected in all seven subjects with nonprogressive infection who were tested. CONCLUSIONS In persons who remain free of disease for many years despite HIV infection the viral load is low, but viral replication persists. Lymph-node architecture and immune function appear to remain intact.