The term “Deaths of Despair” (DoD) refers to mortality due to alcohol consumption, drug use, and suicides. While the concept has predominantly been studied in the United States, where these deaths have increased significantly, this analysis examines its application to Italy, a country with comparatively lower DoD rates. This work aims to analyse the magnitude of these causes of death in Italy and its regional differences. We employ the Potential Gain in Life Expectancy to assess the impact of these causes in Italy. Using ISTAT data from 1983 to 2018 at NUTS1 level, the study reveals the unique dynamics of DoD in Italy and its regional variations. We found a decline in DoD mortality in Italy, driven mainly by a reduction in alcohol-related deaths. Following the economic crisis of 2011, suicides have become the most serious of the three causes of death related to despair, except in the South, where alcohol-related deaths still have the greatest impact on life expectancy. In contrast to the US, drug-related deaths in Italy have a relatively minor impact compared to the other two causes.