A study was conducted to assess the relative contribution of the HIV-1 specific immune response and nonspecific immune activation to HIV disease pregression. The titer of antibody to the p24 core protein and the concentration of serum neopterm were measured in 238 HIV-1 seropositive subjects in a prospective cohort study of homosexual men. Antibody titers were extremely variable among cohort participants but relatively stable over time, suggesting inherent differences in the initial immune response capacity. Neopterin concentrations were also variable at cohort entry but generally in creased over time. These two markers, measured at cohort entry, had powerful and independent predictive value for the development of AIDS up to 54 months before diagnosis. Subjects with low antibody titers and high levels of neopterin, had the highest incidence of AIDS (60% over 54 months). Patients with low antibody or high neopterin alone had an intermediate risk (34% incidence) and less than 10% of those with high antibody and low neopterm developed AIDS. We propose that the initial immune response to HIV and virus-medrated immune system activation are independent and innately variable components of an individual's response to HIV infection that interact to determine the clinical outcome.