To study the dynamics of human immunodeficiency virus (HIV)-1 RNA level around the time of conversion from non-syncytium-inducing (NSI) to syncytium-inducing (SI) phenotype and to study the predictive value of the SI phenotype for progression to AIDS, sequential samples from 123 HIV-infected homosexual men with documented intervals of seroconversion were evaluated. The NSI-to-SI phenotype conversion coincided with a 3-fold increase in median RNA level, which was not observed in matched controls in whom a viral phenotype conversion did not occur. This increase in virus was followed by a decrease to a higher steady-state RNA level than before the switch. After adjusting for RNA level and CD4 T cell count, SI phenotype was an independent marker for progression to AIDS. Hence, phenotype determination will contribute to optimal staging of HIV-infected persons in addition to virus load measurements and CD4 T cell count.