The burnout syndrome is characterized by emotional exhaustion, depersonalization, and lack of personal accomplishment. It was identified in some professional categories, the most often being affected those in public health services. This study mainly aims to identify and analyze the value of the personality traits and work characteristics as predictive factors for the occurrence of the burnout syndrome in nurses, under the new approach of predictive, preventive, and personalized medicine. A total of 192 nurses were included in the study. The NEO-Five-Factor Inventory, the Copenhagen Burnout Inventory, and the Inventory of Nursing Work Characteristics were administered to all of the participants. Some personality traits proved to be predictive factors for the occurrence of the burnout syndrome. Neuroticism, negative self-esteem, and negative emotionality predict burnout vulnerability. The negative correlations between sociability and the burnout dimensions show that the positive affectivity of the extraverted individuals and the strong positive orientation of the extraverts towards others are protective factors against burnout. There are also significant associations between certain personality traits and nursing work characteristics (work overload, the existence of problems in the department, and satisfaction in the professional and family life), which could be defined, also, as predictive factors for burnout. This study confirms the influence of the Big Five personality traits and nursing work characteristics as predictive factors of the burnout occurrence, opening real possibilities to perform a targeted prevention and provide personalized interventions as organizational services.