We assessed the value of HIV-1 RNA level compared to soluble immune activation markers, namely neopterin, beta2-microglobulin and soluble TNF receptor 75 (sTNFR-75), to predict the change in the number of CD4+ T cells over a 1-year period, the development of AIDS, and survival (median follow-up 54 months). The study population comprised a cohort of 47 individuals for the analysis of the change in CD4+ T cells and survival (20 died), and a subgroup of 31 individuals with a baseline CD4+ T cells above 200 x 10(6)/l for the development of AIDS (11 developed AIDS). HIV-1 RNA was measured from stored sera by quantitative PCR. The CD4+ T cell count obtained at study entry strongly correlated with baseline serum HIV-1 RNA levels (r=-0.47), and to a lesser extent with neopterin (r=-0.41) and beta2-microglobulin (r=-0.29). The percentage change in CD4+ T cells over a 1-year period correlated with HIV-1 RNA levels (r=-0.32, p=0.03), however, stronger correlations were found for neopterin, beta2-microglobulin and sTNFR-75 (r=-0.51, r=-0.41, r=-0.42; p< 0.01). No progression to AIDS or death was observed in individuals with baseline HIV-1 RNA levels below 20,000 copies/ml (10 of 31 and 15 of 47 individuals, respectively). A Cox's proportional hazard model to predict AIDS revealed that HIV-1 RNA, the change in CD4+ cells over a 1-year period and sTNFR-75 levels independently predict AIDS; the change in CD4+ cells, the absolute CD4+ T cell count and neopterin were jointly significant to predict death. All results were adjusted for nucleoside monotherapy. In conclusion, to improve the predictive power, quantitation of HIV-1 RNA as a 'natural history marker' may be supplemented by measurement of sTNFR-75 for 'early'-stage disease progression and neopterin for 'late'-stage disease progression.