In this paper, the objectives, design, data-collection procedures and enrollment rates of the Longitudinal Study on Socio-Economic Health Differences (LS-SEHD) are described. This study started in 1991, and is the first large-scale longitudinal study of the explanation of socio-economic inequalities in health in the Netherlands. The LS-SEHD aims at making a quantitative assessment of the contribution of different mechanisms and factors to the explanation of socio-economic inequalities in health. It is based on a research model incorporating both 'selection' and 'causation' mechanisms, and a wide range of specific factors possibly involved in these mechanisms: health-related life-style factors, structural/environmental factors, psychosocial stress-related factors, childhood environment, cultural factors, psychological factors, and health in childhood. The design of the LS-SEHD is that of a prospective cohort study. An aselect sample, stratified by age, degree of urbanization and socio-economic status, for approx. 27,000 persons was drawn from the population registers in a region in the Southeastern part of The Netherlands. The persons in this sample received a postal questionnaire. An aselect subsample of approx. 3500 persons from the respondents to the postal questionnaire was, in addition, approached for an oral interview. The follow-up of these samples will use routinely collected data (mortality by cause of death, hospital admissions by diagnosis, cancer incidence), as well as repeated postal questionnaires and oral interviews. The response rate to the base-line postal questionnaire was 70.1% (n = 18,973), and that to the base-line oral interview was 79.4% (n = 2802). If the LS-SEHD is compared to a number of frequently cited longitudinal studies of socio-economic inequalities in health from the United Kingdom, it appears that the differences with the OPCS Longitudinal Study and the birth cohort studies (such as the National Survey of Health and Development) are huge. The LS-SEHD is more akin to the Whitehall(I)-study and the West of Scotland 20-07 study. For example it has the sample size of the former but the open population and emphasis on social factors of the latter. A comparison of the results of various longitudinal studies of socio-economic inequalities in health is recommended.