Background. Human immunodeficiency virus type 1 (HIV-1) coreceptor tropism, the ability of the virus to enter cells via CCR5 or CXCR4, is a viral characteristic mediated by the envelope gene. The impact of coreceptor tropism on the natural history of HIV-1 infection has not been fully explored. Methods. Coreceptor tropism was measured using a recombinant virus single-cycle assay on plasma specimens obtained at baseline from 126 children and adolescents in the Hemophilia Growth and Development Study cohort who were enrolled from 1989 through 1990 and underwent follow-up through 1997. Results. Detectable CXCR4-using virus at baseline was associated with a lower baseline CD4+ T cell count and a higher plasma HIV-1 RNA level. In addition, it independently predicted a greater decrease in CD4+ T cell count over time (P < .001) and was associated with a 3.8-fold increased risk of progression to clinical AIDS. Conclusions. This study demonstrates that coreceptor tropism, as assessed by this single-cycle assay, independently influences the natural history of HIV-1 disease.