The relationship between the evolution of human immunodeficiency virus type 1 (HIV-1) biologic phenotype, changes in the proportion of infected peripheral blood mononuclear cells, and the relative contribution of non-syncytium-inducing (NSI) and syncytium-inducing (SI) HIV-1 variants to virus load was studied during the course of HIV-1 infection. In 65 HIV-1-infected subjects, the proportion of infected CD4 T cells was higher in persons who carried SI variants. Longitudinal studies revealed that the emergence of SI HIV-1 variants can occur at relatively low numbers of HIV-1-infected cells. Emergence of SI variants frequently coincided with an increase of virus load due to an expansion of both NSI and SI variants, although the contribution of SI viruses to the total virus population significantly increased with time after SI phenotype conversion. These data indicate that NSI to SI phenotype conversion, rather than resulting from high virus load, is part of the sequence of events that leads to increased virus load and CD4 cell depletion.