Objective: To measure the burden of the COVID-19 pandemic in 2020 at the subnational level by estimating excess mortality, defined as the increase in all-cause mortality relative to an expected baseline mortality level.

Design: Statistical and demographic analyses of regional all-cause mortality data.

Participants: The entire population of 561 spatial units in 21 European countries.

Main Outcome Measures: Losses of life expectancy at ages 0 and 60 for males and females.

Results: Evidence was found of a loss in life expectancy in 391 regions, while only three regions exhibit notable gains in life expectancy in 2020. For 12 regions, losses of life expectancy amounted to more than 2 years, and three regions showed losses greater than 3 years. Geographic clusters of high mortality were found in northern Italy, Spain and Poland, while clusters of low mortality were found in western France, Germany/Denmark and Norway/Sweden.

Conclusions: Regional differences of loss of life expectancy are impressive, ranging from a loss of more than 4 years to a gain of 8 months. These findings provide a strong rationale for regional analysis, as national estimates hide significant regional disparities.