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Background: Cofactors associated with persistently abnormal CD4 + :CD8 + T-cell ratio in people with HIV (PWH) on antiretroviral treatment (ART) might change over time as the population of people with HIV ages or as new ART drugs become available. The main objective of our study was to determine the long-term associations of baseline factors, including the CD4 + T-cell count and ratio, with ratio normalization (≥1). In addition to this, we explored whether the ratio remained associated with the risk of both AIDS and non-AIDS events among individuals on suppressive ART., Methods: Clinic-based study in a tertiary, university hospital in Madrid. People with HIV starting a first-line ART regimen (January 2006-June 2017) were included in a prospective national multicentre cohort (CoRIS). People with controlled HIV-infection within the first year of ART initiation and complete CD4 + and CD8 + T-cell records were selected. Cox proportional hazard (PH) regression models were used to estimate the cumulative incidence of ratio normalization and to examine associations with socio-demographic and clinical variables. To investigate factors independently associated with the development of AIDS and non-AIDS events we used a time updated Poisson regression model., Results: The study included 557 subjects. During follow-up (median 5.24 years), 44% of participants achieved a ratio of 1 within a median of 1.49 years. In a multivariate PH model, pre-ART factors negatively associated with ratio normalization were the pre-ART CD4 + :CD8 + T-cell ratio and mode of HIV acquisition. For the secondary analysis, 1.3 events/100 person years of follow-up were observed. After adjustment, older age, HIV RNA >200 copies/ml and CD4 + :CD8 + T-cell ratios over follow-up, remained significantly associated with the development of AIDS and non-AIDS events. In contrast, pre-ART ratio was not associated with the risk of AIDS and non-AIDS events., Conclusions: In summary, our study showed that higher pre-ART CD4 + :CD8 + T-cell ratio is associated with rates of ratio normalization ≥1. In addition, the risk of AIDS and non-AIDS events seems to be predicted by the time updated CD4 + :CD8 + T-cell ratio not by the pre-ART CD4 + :CD8 + T-cell ratio. Therefore, CD4 + :CD8 + T-cell ratio should be considered as a dynamic marker for translation into clinical practice.