We investigated the relationship between CD4(+)CD38(+), CD4(+)HLA-DR+, CD8(+)CD38(+), and CD8(+)HLA-DR+ cell proportions (HLA-DR = major histocompatibility complex class II) (determined by two-color immunofluorescence) and the clinical condition, IL-2 and IL-6 production, viral RNA copy numbers, and the eventual immunologic-virologic course in 25 children perinatally infected with HIV-1 surviving longer than 5 y [median age, 92 (range, 63-136) mo]. Twelve healthy age-matched children were studied as control subjects. HIV-1(+) children had lower percentages and absolute numbers of CD4(+)CD38(+) whereas the percentages of CD4(+)HLA-DR+ and the percentages and absolute numbers of CD8(+)CD38(+) and CD8(+)HLA-DR+ cells were higher than that of control subjects. The absolute numbers of CD4(+) and the percentages of CD4(+)CD38(+) CD8(+)CD38(+), and CD8(+)HLA-DR+ cells directly correlated, whereas the percentages of CD4(+)CD38(+) and CD4(+)HLA-DR+ cells, the percentages of CD4(+)CD38(+) and CD8(+)CD38(+) cells, the CD8(+) cell absolute numbers, and the percentages of CD8(+)CD38(+) cells did not. Severe manifestations and immunologic deterioration occurred in children with low CD4(+)CD38(+) cell percentages, whereas virologic worsening was associated with low CD8(+)CD38(+) and CD8(+)HLA-DR+ cell percentages. IL-2 production directly correlated with percentages and absolute numbers of CD4(+)CD38(+) and CD8(+)CD38(+) cells. RNA copy numbers inversely correlated with CD4(+)CD38(+), CD4(+)HLA-DR+, CD8(+)CD38(+), and CD8(+)HLA-DR+ cell percentages. This suggests that CD38 molecule expression on both CD4(+) and CD8(+) cell subsets is a favorable marker in HIV-1(+) children. Perhaps CD8(+)CD38(+) subsets are activated cells, whereas CD4(+)CD38(+) subsets are immature cells, possibly the host's attempt at CD4(+) cell renewal.