In this study we investigated the mediated influence of core self-evaluations (CSE) on employee health problems via job satisfaction and work stress, and the degree to which genetic factors explain these mediated relationships. Based on data obtained from a sample of 594 Swedish twins (114 monozygotic twin pairs and 183 dizygotic twin pairs), conventional path analysis results supported the mediated effects of CSE on employee health via job satisfaction and work stress, after controlling for conscientiousness and extraversion. Behavioral genetic analyses showed significant heritability of all four variables. Moreover, we found that the mediated relationships via job satisfaction and work stress are explained by genetic factors, such that the genetic source of job satisfaction and work stress mediates the genetic influence of CSE on health problems. These results highlight the role played by genetic factors in better understanding the relationships between CSE, work attitudes, and health outcomes.