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Three phenotypes of the antioxidant protein haptoglobin are known: Hp 1–1, Hp 2–1 and Hp 2–2.To investigate the outcome of HIV infection according to haptoglobin type.Haptoglobin phenotypes were determined using starch gel electrophoresis in serum obtained from 653 HIV-infected Caucasians in the AIDS reference centers of Gent (n = 184), Antwerp (n = 309), and Luxembourg (n = 160). Survival was compared between haptoglobin types using Kaplan-Meier curves. Plasma HIV-1 RNA was quantified by reverse transcriptase PCR. Serum iron, transferrin saturation, ferritin, and vitamin C were assayed to evaluate iron-driven oxidative stress in 184 HIV-infected patients and 204 controls.The haptoglobin type distribution amongst the patients (17.6% Hp 1–1, 49.9% Hp 2–1, 32.5% Hp 2–2) corresponded to that of the controls. Kaplan-Meier curves showed a higher mortality for the Hp 2–2 group (P = 0.0001; adjusted mortality risk ratio, 1.78; 95% confidence interval, 1.25−2.54). Median survival time was 11.0 years (Hp 1–1 and Hp 2–1) versus 7.33 years (Hp 2–2). Plasma HIV-1 RNA levels prior to antiviral therapy and their increase over 1 year were highest in Hp 2–2 patients (P = 0.03 and 0.003, respectively). The Hp 2–2 type was associated with higher serum iron, transferrin saturation, and ferritin levels and with low vitamin C concentrations. Furthermore, ferritin concentrations were higher in HIV-infected patients than in controls (P < 0.0001).HIV-infected patients carrying the Hp 2–2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.