We have investigated the relationship between disease progression and several immunologic and virologic markers of HIV infection. Plasma samples from infants born to HIV-1-infected mothers were collected at birth and at 1, 2, 4, 6, 9, 12, 15, and 18 mo of age and subsequently were assayed every 6 mo for viral load, viral phenotype, and lymphocyte populations. A cutoff level of 25% indicative of a preserved immunologic status, both of CD4+ and CD8+ blood T cells, was associated with significant differences in disease progression (p = 0.04 and 0.02, respectively). Infants with median CD4+ T cells <25% had a relative risk of progression to AIDS 3.35-fold higher than those with CD4+ above this level (p = 0.05). The relative risk of progression to AIDS for infants with median CD8+ <25% was 4.95-fold higher than for those with CD8+ percent above this threshold (p = 0.03). Similarly, a cutoff level of viral load of 5.5 log10 copies/mL was indicative of a worse prognosis. Infants with median viral load >5.5 log10 copies/mL had a relative risk of progression to AIDS 23.72-fold higher (p = 0.0001) than those with median viral load below this threshold. Interestingly, changes from a slow replication and low titer to a rapid replication and high titer of virus and from nonsyncytium-inducing to syncytium-inducing viral phenotype were indicative of progression to AIDS. Our results indicate that biologic phenotype of viral isolates and CD8+ T-lymphocyte percentages in peripheral blood as well as viral load and CD4+ T-lymphocyte percentages could predict rapid progression to advanced HIV-1 disease in HIV-1-infected infants.