Most human immunodeficiency virus (HIV)-infected individuals experience increases in peripheral CD4+ T cell counts with suppressive antiretroviral therapy (ART) that achieves plasma HIV RNA levels that are less than the limit of detection. However, some individuals experience decreasing CD4+ T cell counts despite suppression of plasma viremia. We evaluated 4 patients with a history of CD4+ T cell decline despite successfully suppressive ART, from a median of 719 cells/mm3 (range, 360-1141 cells/mm3) to 227 cells/mm3 (range, 174-311 cells/mm3) over a period of 18-24 months; 3 of the patients were receiving tenofovir and didanosine, which may have contributed to this decrease. There was no evidence of HIV replication, nor of antiretroviral drug resistance in the blood or lymphoid tissue, or increased proliferation or decreased thymic production of naive CD4+ T cells. All 4 patients had significant fibrosis of the T cell zone of lymphoid tissue, which appeared to be an important factor in the failure to reconstitute T cells.