Using a large sample of employed adults (N = 1,714) living in Switzerland, this study investigates the relationship between the five-factor model of personality dimensions and job satisfaction considering the role of job strain as defined by Karasek’s (1979) JDC model and occupational self-efficacy. These relationships were assessed both within the overall sample of employed and specific occupational groups. The analyses on the overall sample show an effect of neuroticism and extraversion on job satisfaction. Furthermore, job strain and occupational self-efficacy are related to job satisfaction. The effect of neuroticism is partly mediated by job strain and occupational self-efficacy, while extraversion and conscientiousness have an indirect effect through occupational self-efficacy. When we consider the occupational groups, the results highlight differences between the groups showing variability in the relationship between personality, job strain and occupational self-efficacy, and their effects on job satisfaction.