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. Methods Statistical and demographic analyses of regional all-cause mortality data provided by the vital statistics systems of 21 European countries for 561 regions in Central and Western Europe. Life expectancy losses at ages 0 and 60 for males and females were estimated. Results We found evidence of a loss in life expectancy in 391 regions, whilst 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. We highlight geographical clusters of high mortality in Northern Italy, Spain and Poland, whilst 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.