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Inflammation in early human immunodeficiency virus type 1 (HIV-1) disease progression is not well characterized. Ninety patients with untreated primary HIV-1 infection were studied to determine associations of inflammatory proteins with early disease progression. High plasma tumor necrosis factor α (TNF-α) levels (≥8.5 pg/mL) were significantly associated with an increased viral load set point and shorter times to reaching a CD4+ T-cell count of <500 cells/mm3 and initiating antiretroviral therapy. The increased risk of reaching a CD4+ T-cell count of <500 cells/mm3 in the group with high TNF-α levels was driven by viral load but was independent of concurrent CD4+ T-cell count. Thus, TNF-α appears to be an important mediator of inflammation in patients with poor viral control and early HIV-1 disease progression.