Virus load and virus phenotype have both been indicated as major determinants of disease progression in HIV-1 infection. In this study HIV-1 RNA copy numbers in serum, virus phenotype, and CD4+ cell counts were analyzed longitudinally in a group of 20 seroconverters progressing to AIDS within 5.5 years. In this group 12 individuals developed AIDS without syncytium-inducing (SI) viruses ever being isolated, while 8 individuals showed a non-SI (NSI) to SI phenotypic switch prior to AIDS development. HIV-1 RNA copy numbers in sera of all progressors were stable and high from seroconversion until development of AIDS. Twenty-one seroconverters remaining asymptomatic for more than 5.5 years were selected as nonprogressing controls, and both progressors and nonprogressors were evaluated at seroconversion and early in infection (3 years post seroconversion). Comparative analysis revealed that at the point of seroconversion HIV-1 RNA copy numbers in sera from NSI progressors, SI progressors, and nonprogressors were not significantly different, nor were their CD4+ cell counts. At seroconversion all individuals harbored viruses with an NSI phenotype. In contrast to the progressors, HIV-1 RNA copy numbers in sera of nonprogressors had declined significantly during the early period of infection. At the second time point RNA copy numbers in the sera of NSI progressors and nonprogressors differed significantly (P = 0.0005), while RNA copy numbers in the sera of SI progressors and nonprogressors did not. However, at this time point the CD4+ cell counts of SI progressors were significantly lower than those from nonprogressors (P = 0.002), while the CD4+ cell counts of NSI progressors and nonprogressors did not differ significantly. These results show that early in HIV-1 infection progressors and nonprogressors are distinguishable. NSI progressors can be distinguished from nonprogressors on the basis of serum HIV-1 RNA load and S1 progressors on the basis of CD4+ cell decline. In addition, a significant decrease in the number of HIV-1 RNA copies in the early phase of infection seems to postpone the development of AIDS.