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. © 2001 Infectious Diseases Society of America.