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We investigated the significance of microbial translocation measured on average 3 years after HIV seroconversion in driving disease progression in HIV+ untreated patients with high CD4+ cell count.We included ICONA patients with documented last HIV-negative and first HIV-positive test, at least one plasma sample stored while antiretroviral therapy (ART)-naive and CD4+ cell count greater than 200 cells/μl.Microbial translocation [lipopolysaccharide (LPS), sCD14 and EndoCAb] and immune activation (IL-6 and TNF-α) were measured. Correlation between immune activation, microbial translocation, CD4+ and plasma HIV-RNA was evaluated by linear regression and nonparametric Spearman's rho. The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, death, CD4+ cell count less than 200 cells/μl or start of antiretroviral therapy (ART) was assessed using survival analysis.We analysed 1488 biomarker measures from 379 patients. A median of 3.1 years after the estimated seroconversion date [interquartile range (IQR) 1.6–5.4], median (IQR) markers values were LPS, 110 pg/ml (IQR 75–215), sCD14, 3.3 μg/ml (2.2–4.8), IL-6, 1.1 pg/ml (0.6–1.9) and TNF-α, 2.4 pg/ml (1.8–3.4). Two hundred and sixty progression events were recorded over a median of 1.6 years from the first sample (2% AIDS, 84% ART initiation, 12% CD4+ cell count less than 200 cells/μl and 2% death). LPS was the only biomarker associated with this primary composite outcome independently of age, HIV-RNA and CD4+ (relative hazard = 1.40 per loge higher, 95% confidence interval 1.18–1.66, P < 0.001).Circulating LPS in the first years of chronic HIV infection is a strong predictor of disease progression independent of CD4+ cell count and HIV viraemia and may be considered a candidate biomarker for HIV monitoring and evaluation in clinical trials.