Aims: The aims of this study were: (1) To examine whether working in a self-directed team is related to home-care nursing staff's job satisfaction; (2) To assess the mediating effect of self-perceived autonomy over patient care; (3) To investigate the moderating effect of educational level on the association between autonomy over patient care and job satisfaction. Background: Self-directed teams are being introduced in home care in several countries. It is unknown whether working in a self-directed team is related to nursing staff's job satisfaction. It is important to gain insight into this association since self-directed teams may help in retaining nursing staff. Design: A cross-sectional study based on two questionnaire surveys in 2014 and 2015. Methods: The study involved 191 certified nursing assistants and registered nurses employed in Dutch home-care organizations (mean age of 50). These were members of the Dutch Nursing Staff Panel, a nationwide panel of nursing staff working in various healthcare settings. Results: Self-direction is positively related to nursing staff's job satisfaction. This relationship is partly mediated by autonomy over patient care. For certified nursing assistants and registered nurses with a bachelor's degree, a greater sense of autonomy over patient care in self-directed teams is positively related to job satisfaction. No significant association was found between autonomy over patient care and job satisfaction for registered nurses with an associate degree. Conclusions: This study suggests that home-care organizations should consider the use of self-directed teams as this increases nursing staff's job satisfaction and may therefore help to retain nursing staff in home care.