To identify factors associated with development of AIDS at high CD4+ cell levels a nested case-control study using data from the Multicenter AIDS Cohort Study (MACS) was conducted. HIV-1-infected men who developed AIDS with > or =300/mm3 CD4+ cells (AIDS men) were compared to men who had > or =300/mm3 of CD4+ cells, but remained AIDS free for at least 2 years. The AIDS men had higher plasma HIV-1 RNA levels (mean 10(5.02) vs. 10(4.42), p<0.01) and neopterin levels (mean 18.3 vs. 11.5 units/ml, p<0.05) before the AIDS diagnosis than did the AIDS-free men. A significantly higher proportion of the AIDS men reported genital herpes within the year prior to their initial AIDS diagnosis than did the AIDS-free men (21.9 vs. 4.4%, p<0.05). The higher viral load at relatively high CD4+ cell levels in men who subsequently developed AIDS within 6 months supports the hypothesis that elevated levels of HIV precede CD4+ decline and are the major factor in determining risk of AIDS even at high levels of CD4+ cell levels.