Objectives: While it is generally accepted that high job strain is associated with adverse occupational outcomes, the nature of this relationship and the causal pathways involved are not well elucidated. We aimed to assess the association between job strain and long-term sickness absence (LTSA), and investigate whether any associations could be explained by validated health measures. Methods: Data from participants (n = 7346) of the Hordaland Health Study (HUSK), aged 40-47 at baseline, were analyzed using multivariate Cox regression to evaluate the association between job strain and LTSA over one year. Further analyses examined whether mental and physical health mediated any association between job strain and sickness absence. Results: A positive association was found between job strain and risk of a LTSA episode, even controlling for confounding factors (HR = 1.64 (1.36-1.98); high job strain exposure accounted for a small proportion of LTSA episodes (population attributable risk 0.068). Further adjustments for physical health and mental health individually attenuated, but could not fully explain the association. In the fully adjusted model, the association between high job strain and LTSA remained significant (HR=1.30 (1.07-1.59)). Conclusion: High job strain increases the risk of LTSA. While our results suggest that one in 15 cases of LTSA could be avoided if high job strain were eliminated, we also provide evidence against simplistic causal models. The impact of job strain on future LTSA could not be fully explained by impaired health at baseline, which suggests that factors besides ill health are important in explaining the link between job strain and sickness absence.