Sense of Coherence (SOC) is a new concept belonging to a salutogenic paradigm, proposing to explain health as contrasted to disease, a pathogenic paradigm. The Job Demand-Control (JDC) model of job stress suggests that the combination of high job demands and low job control, defined as job strain, is strongly associated with adverse health consequences. The aim of this study was to evaluate the relationship between SOC and the JDC model in assessment of negative job effects within three pathogenically defined contexts: self-reported health, burnout and psychophysiological stress indicators, assessing the explanatory value of SOC for such variables. The study was conducted with 103 employees of social-welfare and social-insurance agencies in Sweden. A questionnaire related to job conditions, health and burnout was administered, and blood samples were collected and analysed for serum concentrations of cortisol, prolactin and immunoglobulin G. Multiple-regression models were calculated including variables from all three contexts. In the analyses, a distinction was made between emotional job strain and quantitative job strain. The SOC interacted with emotional job strain, but the interaction also increased the independent effect of emotional job strain. The independent effect of SOC disappeared in most models when interaction was included. It is concluded that studies of job strain-effects according to the JDC model should include the SOC as an interaction factor.