The effectiveness of modern antiretroviral therapies (ART) transformed HIV infection into a chronic disease characterized by a persistent condition of inflammation and immune activation. For this reason, even thought AIDS-related mortality has been reduced with an increased life expectancy, patients living with HIV infection are more likely to develop non-AIDS events despite the achievement of a complete suppression of HIV replication. Hence, the scientific community feels the need to find new biomarkers which would be suitable in clinical practice for identifying patients who require a close monitoring because of an increased risk of developing comorbidities. A renewed interest has emerged about the usefulness of CD4/CD8 ratio as a strong marker of immune activation and immune senescence. Recently, many studies have underlined that CD4/CD8 ratio might represent a good predictor of AIDS and non-AIDS events. Herein, the potential role of the CD4/CD8 ratio for the monitoring of HIV patients in different clinical settings is reviewed.