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AIMS AND OBJECTIVES To investigate how nurses who worked in Guangdong province in China perceived empathy, nursing organization climate and burnout. DESIGN A cross-sectional quantitative research design was used. We carried out the research in accordance with the Strengthening the Reporting of Observational studies in Epidemiology checklist. METHODS The study was carried out from August-October of 2018 using a structured electronic questionnaire. A total of 965 participants were selected with convenience sampling in Guangdong province. RESULTS A total of 786 valid questionnaires were collected in this study. The average burnout score of participants was 38.19 (SD 13.32) and 67.4% of them rated their burnout as more than 30 points, while 5.7% were higher than 60 points. The multi-variable linear regression model explained 9.4% of the variance in burnout related to sociodemographic variables (p < 0.001). Empathy was significantly and positively associated with nursing organizational climate and emotional exhaustion while negatively associated with reduced personal accomplishment. In addition, nursing organizational climate mediated the relationship between empathy and reduced personal accomplishment. CONCLUSION Our findings suggest that both empathy and nursing organizational climate are protective factors that prevent burnout in this population. Managers can alleviate nurses' burnout through developing empathy and improving the organizational climate. IMPACT This study demonstrates that empathy is not the cause of burnout; rather, it can prevent nurses from experiencing burnout. Nursing organizational climate is another protective factor that has a mediating effect on empathy and burnout. Improving empathy and nursing organizational climate could help reduce nurse burnout.