A dissociation between plasma human immunodeficiency virus (HIV) RNA levels and CD4(+) cell counts has been reported in patients experiencing viral relapse while receiving antiretroviral therapy. This study compared patients with stable CD4(+) lymphocytes during viral relapse while receiving treatment with patients who had sustained virus suppression. Plasma HIV RNA levels, lymphocyte immunophenotyping, and T cell receptor excision circle (TREC) levels were measured. Naive CD4(+) lymphocyte phenotype and TREC levels were not significantly different in patients with virus suppression or in those who had relapsed. However, CD8(+) lymphocyte activation, including the number and percentage of activated cells and CD38 antibody-binding capacity, was significantly elevated during viral relapse, compared with that in suppressed patients. By multivariable regression analyses, CD8(+) and CD4(+) lymphocyte activation were associated significantly with increasing plasma HIV RNA levels.