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Introduction: The reversal of CD4/CD8 ratio is considered an independent predictor of death in the general population, where the ratio physiologically decreases with aging. Despite effective cART, CD4/CD8 normalization does not always occur in HIV-positive subjects. In the setting of HIV, low CD4/CD8 T-cell ratio correlates with immune activation and non-AIDS events. The aim of the study was to evaluate the rate and predictors of CD4/CD8 ratio normalization in a cohort of HIV-positive subjects starting combination antiretroviral therapy (cART)., Methods: This is a retrospective-prospective observational cohort study conducted at the Unit of Infectious Diseases of the University of Catania. Our cohort included naive individuals who initiated cART from January 2007 to December 2013., Results: A total of 123 individuals were enrolled. The median age was 38 years (IQR 29-44). The median baseline CD4+ T-cell count was 288 cells/μl (IQR 105-400). 83 (67.5%) had a CD4+ T-cell count <350/μl; baseline median CD4/CD8 ratio was 0.24 (IQR 0.13-0.4); 65 patients (52.8%) had a HIV viral load >100,000 copies/ml. At 24 months, 33 individuals (26.8%) normalized their CD4/CD8 ratio, with a median time to CD4/CD8 ratio normalization of 17 months (IQR 12-30). In univariate analysis, a baseline CD4+ T-cell count >350/μl (p <0.01), a baseline CD4/CD8 ratio >0.5 (p <0.01), CDC stage A (p<0.01) and an efavirenz-based first-line regimen (p<0.05) were associated with CD4/CD8 ratio normalization. In multivariate logistic analysis, the only predictor of CD4/CD8 normalization was a baseline ratio >0.5 (OR 4.3 (1.7-11.2), p=0.003)., Conclusion: Starting cART with a ratio >0.5 is associated with an increased likelihood to normalize CD4/CD8 ratio. Early diagnosis should be encouraged in order to treat patients promptly and favor a more robust immunological reconstitution.