In the present investigation a psychosocial theory of sick leave is proposed which integrates work-related determinants, health effects of particular work characteristics, and workers' health status. In addition, the theory explicitly formulates a series of mediators and moderators of the associations between work-related determinants and sick leave. On the basis of the theoretical assumptions and previous research findings, a series of research hypotheses are investigated with survey data. The study is based on data from the European Working Conditions Survey 2010 and 2015 (n = 59,790). The research hypotheses are investigated by means of generalised linear mixed models within the framework of hierarchical Bayesian regression models and Markov Chain algorithms. The theory is assessed by estimating three so-called hurdle models, which take into account the excess zeros usually observed in sick leave rates. In general, the findings provide evidence of the adequacy of the theory explaining the observed variation of sick-leave rates. Several biomechanical and psychosocial characteristics of the working environment, occupation, age, and the subjective assessment of health status were found to be strongly associated with both the likelihood of being in sick leave and the length of sick-leave spells. The theory and the findings of the present study may serve as a basis for the development and implementation of occupational health interventions aiming to reduce sick-leave rates in organisations.