The aim of this study was to evaluate the effects of locus of control and work-related stress on burnout in hospital staff nurses. A convenience sample of 361 staff nurses from nine units in five German hospitals were surveyed using the Maslach Burnout Inventory, the Locus of Control Questionnaire and a Work-Related Stress Inventory. Causal modeling was used to explore the moderating effect of locus of control on burnout. Results support the hypothesized model and suggest that greater work-related stress and burnout would be associated with poorer locus of control in nurses. The findings supported the notion that perceived degree of control is instrumental in enabling nurses to cope with stress and burnout.