Aim: The Lolland-Falster Health Study (LOFUS) is an ongoing prospective cohort study at Lolland-Falster, one of the most socio-economically disadvantaged areas of Denmark. The aim of this study was to examine the participation rates and socio-economic determinants of participation in LOFUS, approximately halfway through the data collection. Subjects and methods: LOFUS started in 2016 and should include 20,000 participants from the total of 103,000 inhabitants of Lolland-Falster by the end of 2019. For the participation analyses, we used data on the 36,883 subjects invited between January 2016 and November 2018. For the analyses of determinants of participation, we used data on the 24,283 adults (aged ≥ 18 years) invited between January 2016 and June 2018, for whom we extracted data on personal income, employment, education, marital status, citizenship, and household type from Danish registers. We used logistic regression to estimate associations between socio-economic factors and participation, adjusting for age and gender. Results: 34.1% of invited subjects participated (men: 31.9%, women: 36.4%), with the highest rate in women aged 60–69 years (47.5%) and the lowest in women aged ≥ 90 years (7.3%). Odds ratios for participation increased with income, education level, and employment status, and among married persons, Danish citizens, middle-aged persons (aged 50–69 years), and women. Conclusion: Subjects with lower socio-economic status were underrepresented halfway through the LOFUS data collection, in line with other cohort studies.