The kinetics and effects of in vivo spontaneous apoptosis and activation-induced cell death (AICD) upon CD4+ and CD8+ lymphocyte subsets and CD4 naive cell numbers were studied in HIV+ subjects with CD4 pretreatment values > 200/mm3, who were subsequently treated for 48 weeks with HAART alone or in combination with six cycles of subcutaneous IL-2. Irrespective of the type of treatment, patients showed a statistically significant increase in CD4 cell counts after 4 weeks, although the CD4 naive subset only increased significantly in the IL-2-treated subjects at the end of treatment. The percentage of CD4 cells undergoing spontaneous apoptosis and AICD was significantly reduced in all patients after 4 weeks and this reduction was maintained until the end of therapy; however, the level always remained significantly higher in comparison with healthy subjects. A statistically significant reduction in CD8 apoptosis levels required at least 24 weeks of therapy. Together these data suggest that a reduction in the level of apoptosis may contribute to the early rise in CD4 numbers measured after HAART, but that later on HAART is unable to improve further this biological parameter. Although the use of IL-2 had no additional effects on spontaneous apoptosis and AICD, it may be beneficial by stimulating a late increase in the numbers of CD4 naive cells in HIV-treated subjects.