CD38 expression on CD8(+) T cells was longitudinally assessed in 31 human immunodeficiency virus (HIV)-infected persons with undetectable plasma viremia who had undergone highly active antiretroviral therapy (HAART) for 12 months and were followed for a mean of 30 months thereafter. Overall, CD4(+)T cell counts increased during follow-up, whereas CD38 expression remained stable. However, a subset of patients showed declines in CD38 expression, and, conversely, another subset showed increases in CD38 expression. No association could be found between long-term gains in CD4(+) T cells and evolution of CD38 expression. Thus, activation of CD8(+) T cells does not seem to be associated with the extent of CD4(+) T cell recovery beyond the first year of successful HAART.