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Work-related psychosocial factors may precipitate the onset of depression. In occupational mental health research, there are three widely used theoretical models, namely, job demand and control (JD-C), effort-reward imbalance (ERI) and work-family conflicts (WFC). However, the interaction between these models and their combined effect on the risk of major depression in the workplace is largely unknown. The aim of this study is to examine the longitudinal combined effects of JD-C, ERI and WFC on the risk of major depression in the working population.Longitudinal data (2008-2013) were collected on randomly selected participants (n=4200) from the working population of the province of Alberta, Canada, at baseline and 1-, 2-, 3- and 4-year follow-up. Data about JD-C, ERI, WFC and major depression were collected by trained interviewers using a computer-assisted telephone interviewing method. Generalised estimating equations for longitudinal modelling were used.There was an independent association between high ERI and high WFC at tx and major depression at tx+1 (OR 1.56, 95% CI 1.25 to 1.96; OR 1.33, 95% CI 1.16 to 1.52), respectively. The combined effects of JD-C and ERI, ERI and WFC, and WFC and JD-C on the risk of major depression were as follows: OR 1.71, 95% CI 1.22 to 2.42, OR 2.47, 95% CI 1.99 to 3.49 and OR 2.21, 95% CI 1.48 to 3.30, respectively. The relative excess risks attributable to the interactions were statistically non-significant.Work-related psychosocial factors are associated with increased risk of major depression over time, but their combined effect is not synergistic. The effects of the factors depicted in the three occupational health models on the risk of major depression appear to be additive.