Introduction: Lolland-Falster is a rural area in south-eastern Denmark that scores unfavourable in health surveys and has the lowest life expectancy in the country. To determine the origin of poor health in Lolland-Falster, we investigated impact on mortality of long-term population movements. Methods: We used data from the Danish Central Population Register 1968–2017 to track movements in and out of Lolland-Falster. This enabled us to calculate mortality based on tenure of residence. Poisson regression adjusted for sex, 5-year age-groups, and calendar year; separately for men and women; and ages <30, 30–64 and ≥ 65 years; was reported as mortality rate ratios (MRR) with 95% confidence intervals (95% CI). Results: Until 1988, mortality in Lolland-Falster was fairly similar to that in the rest of Denmark. Hereafter, mortality rates drifted apart. In 2008–2017, MRR of the total Lolland-Falster population was 1.21 (95% CI: 1.19–1.23). In each 10-year calendar period, people recently in-migrating constituted about one fourth of the population. MRRs of the in-migrating population increased over time from 1.17 (95% CI: 1.08–1.26) in 1968–1977, to 1.82 (95% CI: 1.75–1.89) in 2008–2017. Persons aged 30–64 constituted the largest in-migrating group and had highest excess mortality, MRR 2.34 (95% CI: 2.19–2.50) in 2008–2017. Conclusion: Long-term selective in-migration of vulnerable persons was behind the gradual build-up of the currently high mortality in Lolland-Falster compared to the rest of Denmark. In particular, people of working age in-migrating to Lolland-Falster contributed to this disparity.