Objective: To examine the effect of work-related psychosocial exposures on long-term sick leave (LTSL) in the general working population. Methods: A prospective study of the general working population in Norway. Eligible respondents were interviewed in 2009 and registered with at least 100 working days in 2009 and 2010 (n = 6758). The outcome was medically confirmed LTSL of 40 days or more during 2010. Results: In the fully adjusted model, high exposure to role conflict (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.20 to 2.09), emotional demands (OR, 1.32; 95% CI, 1.03 to 1.69), and low supportive leadership (OR = 1.50; 95% CI, 1.15 to 1.96) predicted LTSL. A test for trend was statistically significant for all factors (P ≤ 0.05). We estimated that 15% of LTSL cases were attributable to these factors. Conclusions: This study underlines the importance of taking into account psychosocial exposures as risk factors for LTSL.