The aim of this cross-sectional study was to explore the main, mediating and moderating role of sense of coherence (SOC) on stress symptoms and on the association between perceived psychosocial work environment and stress symptoms. The sample includes 2053 Danish employees from 52 workplaces. Hierarchical regression models were applied for each measure of stress. The results strongly supported the presence of a main effect for SOC. People with high levels of SOC experienced fewer stress symptoms. A mediating effect of SOC was also supported. Thus, SOC in part explained the association between work environment and stress symptoms. In addition, some support for a moderating effect of SOC was found, suggesting that people with higher SOC coped more efficiently with work environmental strain that people with lower SOC. Taken together the regression models explained 11-32% of the variance in stress symptoms. The results suggest that measures of individual factors such as SOC should be included in analyses of the effects of work environmental factors on stress and well-being.