Increased expression of CD38 on CD8+ T cells is associated with activation of the immune system, progression of HIV disease, and death in adults. The prognostic significance of these cells in HIV-infected children, where the picture is complicated by age-related differences in CD38 expression, remains controversial. Measuring the unimodal expression of CD38 on CD8+ T cells in adults and children by flow cytometry is best accomplished by quantitating the antigen on the cell surface. To our knowledge, this technique has not previously been reported in a pediatric population. Vertically HIV-infected children were age matched for mild (n = 26) and severe (n = 23) clinical disease. Eleven age-matched HIV-negative controls were included for comparison. Quantitation of CD38 on CD8+ T cells was performed at baseline and 1 y later. The ages of the children in the three clinical groups did not differ significantly (p = 0.6004). HIV-infected children had significantly increased CD38 measurements in comparison with the HIV-negative controls (p = 0.0131), and the severe disease group tended to have higher measurements than the mild disease group. Increased CD38+CD8+ T cells were significant predictors of death within the first year (p = 0.043). These findings support the view that increased CD38 expression on CD8+ T cells has the same prognostic significance in pediatric as in adult HIV disease.