This study among 115 US and 260 Dutch nurses and nurse assistants tested a theoretically derived model of specific relationships between work characteristics and two theoretically distinct outcomes (i.e., emotional exhaustion and job satisfaction). Furthermore, the mediating role of negative work-home interference (NWI) in this context was examined. It was hypothesized that emotional exhaustion is related to job demands (i.e., psychological and emotional demands), and that job satisfaction is primarily associated with job resources (i.e., job control). Workplace social support was proposed to relate to both outcomes. In addition, we expected NWI to partially mediate the hypothesized relationships. Finally, we expected this pattern to be similar across the two samples. Structural equation modeling (LISREL) indicated (1) that our postulated model largely fitted to the data in both samples (same pattern), and (2) that NWI partially mediated the relationship between psychological job demands and emotional exhaustion in the Dutch sample. It can be concluded that the results supported our proposed pattern of specific relationships and, to a lesser extent, the partial mediating role of NWI. Practical implications and methodological limitations were discussed.