Currently, AIDS or severe immunodeficiency remains as a challenge for people with HIV (PWHIV) and healthcare providers. Our purpose was to analyze the impact of advanced HIV disease (AHD) on mortality, life expectancy and health-related quality of life (HRQoL). We reviewed cohort studies and meta-analyses conducted in middle- and high-income countries. To analyze HRQoL, we selected studies that reported overall health and/or physical/mental health scores on a validated HRQoL instrument. AIDS diagnosis supposes a higher risk of mortality during the first six months, remaining higher for 48 months. It has been reported that cancer and cardiovascular disease persist as frequent causes of mortality in PWHIV, especially those with previous or current AHD. PWHIV who initiate combination antiretroviral therapy (cART) with CD4 < 200 cells/µL have significantly lower estimated life expectancy than those with higher counts. AHD is associated with lower HRQoL, and a worse physical health or mental health status. AIDS and non-AIDS defining events are significant predictors of a lower HRQoL, especially physical health status. AHD survivors are in risk of mortality and serious comorbidities, needing special clinical attention and preventive programs for associated comorbidities. Their specific needs should be reflected in HIV guidelines.