BACKGROUND Recent meta-analyses have found that mindfulness practice may reduce anxiety and depression in clinical populations and there is growing evidence that mindfulness may also improve well-being and quality of care in health professionals. This study examined whether mindfulness protects against the impact of work-related stress on mental health and burnout in emergency room (ER) nurses. METHODS ER nurses (N=50) were recruited from an urban teaching hospital in Switzerland and completed a survey on work-related stressors, mindfulness, burnout, depression, and anxiety. Results: The most frequently reported work-related stressor was interpersonal conflict. Nurses working more consecutive days since last taking time off were at greater risk for depression and those reporting more work-related interpersonal conflicts were at greater risk for burnout. Mindfulness was associated with reduced anxiety, depression, and burnout. Mindfulness was a significant predictor of anxiety, depression, and burnout and moderated the impact of work-related stressors on mental health and burnout. LIMITATIONS The sample is limited to nurses and results need to be replicated in other groups (e.g., medical staff or ambulance workers). We assessed clinical symptoms with questionnaires and it would be desirable to repeat this assessment with clinical diagnostic interviews. Conclusions: The findings have implications for stress management in ER nurses and health professionals working in comparable settings (e.g., urgent care). The robust associations between mindfulness and multiple indices of psychological well-being suggest that ER staff exposed to high levels of occupational stress may benefit from mindfulness practice to increase resistance to mental health problems and burnout.