Research has extensively identified empathic skills as essential in health trainings, policies, and recommendations. However, there have been conflicting views of the impact of empathy on burnout. Some studies contend that empathy serves a protective role, whereas other studies have shown that burnout leads to a diminished capacity to empathize. To date, studies have not yet explored whether defense styles mediate associations between empathy and burnout. A total of 442 nurses completed questionnaire measures of empathy, burnout, and defense mechanisms as part of a large-scale research study on nurse burnout. Findings reflected very high levels of emotional exhaustion and depersonalization among the nursing staff. The nurses in this study endorsed a predominantly immature defense style. In addition, immature defense styles mediated the association between empathy and emotional exhaustion and between empathy and depersonalization. The study provides further knowledge about the role of defense styles in nurse burnout and empathy.