The purpose of this study was to determine whether soluble CD8 (sCD8) in serum of perinatally human immunodeficiency virus 1 (HIV-1)-infected children during the first year of life differs from that of HIV-1-uninfected control children. Soluble CD8 concentrations in stored plasma and serum samples of children of HIV-1-infected and uninfected mothers were determined using a sandwich immune assay. In the first month of life significantly greater concentrations of sCD8 occurred in 12 HIV-1-infected infants than in 9 uninfected infants born to infected mothers (mean = 1054, SD 540vs.589, SD 370 units/ml,P< 0.05), although the CD8+ T cell proportions were not different (21.7vs.21.1,P> 0.5). The differences in sCD8 concentrations was most pronounced in 8 infants who were HIV-1 culture positive on initial testing in the first week of life compared with the remaining 4 patients when virus was first detected on subsequent analysis (mean = 1315, SD 446vs.529, SD 231 units/ml,P< 0.01). The concentration of sCD8 was also greater in 26 HIV-1-infected children than in either 26 uninfected children born to infected mothers or 25 seronegative children during the first year of life (mean = 1268, SD 529vs.630, SD 290vs.553, SD 315 units/ml,P< 0.05). Early and persistent elevation in sCD8 probably reflects immune activation resulting from HIV-1 infection. The occurrence of this increase in the neonatal period may reflect prenatal viral transmission, a higher viral inoculum or coinfection with other agents stimulating immune activation.