Background <p>The term “Deaths of Despair” (DoD) refers to mortality due to alcohol consumption, drug use, and suicides. While extensively studied in the United States, where these deaths have markedly increased, less is known about their patterns in other contexts. This study explores the relevance of this concept to Italy, a country with comparatively lower rates, to determine whether these causes of death exhibit common trends and can be meaningfully grouped under a single category.</p> Methods <p>We use cause-specific mortality data from the Italian National Institute of Statistics covering the period 1983 to 2018. Data are aggregated by gender and five-year age groups at the NUTS1 regional level. The Potential Gain in Life Expectancy is used to assess the impact of each cause on overall mortality. To explore potential long-term relationships between the causes and across regions, we apply Cointegration Analysis to the time series.</p> Results <p>The analysis shows a general decline in mortality from causes typically associated with despair in Italy, mainly driven by a reduction in alcohol-related deaths. Drug-related mortality and suicide show more heterogeneous trends across regions and over time. Cointegration Analysis reveals no evidence of long-term dependency among these causes or across regions, with only a few exceptions. This indicates that the observed causes do not share a common underlying temporal structure.</p> Conclusions <p>Findings suggest that in the Italian context, deaths from alcohol, drugs, and suicide do not follow a unified pattern and should not be treated as a single category. Rather, they represent distinct public health issues with different regional trajectories and determinants. As such, they require targeted and differentiated policy responses rather than a unified approach.</p>