Objectives The aim of this study was to investigate the individual, joint and interactive effects of job strain and informal caregiving on long-term sickness absence with special attention to gender differences. Methods The study comprised a prospective cohort study of 6798 working adults from France, 14 727 from Finland, and 5275 from the UK. A total of 26 800 participants, age 52 (interquartile range 47-56) years participated in the study. Job strain was assessed using the demand-control model. Informal caregiving was defined as care for a sick, disabled, or elderly person. Long-term sickness absence spells defined as absence >14 consecutive days were registered during two years follow-up. We used recurrent-events Cox regression in random-effects meta-analyses. Results A total of 12% men and 21% women had ≥1 long-term sickness absence spell. Among women, both high job strain [hazard ratio (HR) 1.08, 95% confidence interval (95% CI) 1.00-1.17] and informal caregiving (HR 1.13, 95% CI 1.04-1.23) were associated with a modestly higher risk of sickness absence. Women doubly exposed to high job strain and informal caregiving also showed a moderately higher risk of sickness absence (HR 1.20, 95% CI 1.03-1.41), but the excess risk was not more than expected from joint exposure to caregiving and job strain. Neither job strain nor informal caregiving predicted sickness absence for men. Conclusions High job strain and informal caregiving predicted long-term sickness absence among women. However there was no noticeable interaction in the presence of both exposures.