BACKGROUND: The aim of this study is to assess the impact of combined work and family demands on all-cause sickness absence and to examine variation in this relationship by occupational grade and gender. METHODS: The study sample consists of 13,179 employees of Electricité de France-Gaz de France (EDF-GDF) who were members of the GAZEL occupational cohort in 1995. Combined work and family demands are assessed based on measures of job strain and number of dependants assessed at baseline (1995). Covariates include occupational grade and demographic, behavioural and social variables assessed at baseline. Ratios of sickness absence days to total person-days contributed by each employee were established from administrative data between baseline and the end of follow-up in 2003. Rate ratios across levels of work-family demands were then calculated. Effect modification by gender and grade of employment was tested. RESULTS: In fully adjusted models, individuals with the highest work-family demands had a rate ratio of sickness absence of 1.78 (95% CI 1.47-2.14) compared with low-demand workers. This association was independent of occupational grade and did not vary with gender. Results were not attributable solely to psychiatric sickness absences. CONCLUSION: High work-family demands at baseline predict long-term all-cause sickness absence across a socio-economically diverse occupational cohort.