HIV-1 RNA levels measured during early chronic infection strongly predict subsequent clinical events. In the short term, HIV-1 is in a steady state, but the stability of viral levels over time is incompletely understood. We used reverse transcriptase polymerase chain reaction (RT-PCR) to examine changes in serum HIV-1 RNA levels in 111 HIV-1-infected homosexual men during the period from 1982 to 1992 and their relation to clinical outcomes. HIV-1 RNA levels increased by a median of 0.08 log10 copies/ml/year (p=.0001). HIV-1 RNA levels rose either gradually or abruptly for the majority of subjects; 41% had no increase. Among subjects surviving at least 8 years, HIV-1 RNA was stable during the first 4 years after seroconversion (median. 0.00 log10 copies/ml/year), but rose in years five through eight (median, 0.06 log10 copies/ml/year; p=.04). The annual HIV-I RNA level was more predictive of AIDS (relative hazard [RH], 1.75 per 0.5 log difference; 95% confidence interval [CI], 1.38-2.21; likelihood ratio [LR], 26.2) than the initial level alone (RH, 1.39; 95% CI. 1.10-1.76; LR, 8.5). We conclude that most HIV-1-infected persons lack a long-term viral setpoint and that failure to account for evolution of the viral level can lead to underestimation of the risk of progression.