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Limited data on acute-phase C-reactive protein (CRP) levels in human immunodeficiency virus (HIV) infection exist.We obtained a single measurement of CRP from 513 HIV-infected men in the Multicenter AIDS Cohort Study to examine the association between CRP and immune suppression and progression to AIDS. We estimated changes in CRP during the course of HIV infection in 81 of these individuals using specimens collected from October 1, 1984, to December 31, 1996.The cross-sectional associations between log10 CRP were correlated inversely with CD4 lymphocyte counts (r = −0.17; P<.001) and directly with log10 HIV RNA levels (r = 0.20; P<.001). Levels of CRP of more than 2.3 mg/L were associated with a decreased time to the development of AIDS (relative time to AIDS, 0.36; P<.001) compared with individuals with CRP levels of 1.2 mg/L or less, which remained significant after adjustment for CD4 lymphocyte counts and HIV RNA and hemoglobin concentrations. Levels of CRP significantly increased over time with mean slopes of 8.5% (95% confidence interval, 4.9%–12.2%) and 4.5% (95% confidence interval CI, 2.1%–6.9%) per year for individuals with and without progression to AIDS, respectively. Individuals had a geometric mean CRP level of 2.5 mg/L in the 6-month interval before progression to AIDS, which was an increase from a nadir of 1.0 mg/L at 6.5 years before progression to AIDS.Levels of CRP were associated with HIV disease progression independent of CD4 lymphocyte counts and HIV RNA levels. In addition, regardless of progression to AIDS, HIV-infected individuals had a significant increase in CRP over time. This may have implications for cardiovascular disease among HIV-infected individuals.