Background: Lolland-Falster is a rural area of Denmark, where the life expectancy is presently almost six years lower than in the rich capital suburbs. To determine the origin of this disparity, we analysed changes in mortality during 50 years in Lolland-Falster. Methods: Annual population number and number of deaths at municipality level were retrieved from StatBank Denmark and from Statistics Denmark publications, 1968–2017. For 1974–2017, life expectancy at birth by sex and 5-year calendar period was calculated. From 1968 to 2017, standardised mortality ratio (SMR) for all-cause mortality was calculated by sex, 5-year calendar period and municipality, with Denmark as standard and including 95% confidence intervals (CI). Results: In 1968–2017, life expectancy in Lolland-Falster increased, but less so than in the rest of Denmark. Fifty years ago, Lolland-Falster had a mortality similar to the rest of Denmark. The increasing mortality disparity developed gradually starting in the late 1980s, earlier in Lolland municipality (western part) than in Guldborgsund municipality (eastern part), and earlier for men than for women. By 2013–2017, the SMR had reached 1.25 (95% CI 1.19–1.31) for men in the western part, and 1.11 (95% CI 1.08–1.16) for women in the eastern part. Increasing mortality disparity was particularly seen in people aged 20–69 years. Conclusions: This study is the first to report on increasing geographical segregation in all-cause mortality in a Nordic welfare state. Development of the mortality disparity between Lolland-Falster and the rest of Denmark followed changes in agriculture, industrial company closure, a shipyard close-down, administrative centralisation, and a decreasing population size.