Abstract: The experience of working on the frontlines of the COVID-19 healthcare crisis has presented a cumulative traumatic experience that affects healthcare professionals’ well-being. Psychological resources such as resilience and adaptive defense mechanisms are essential in protecting individuals from severe stress and burnout. During September 2020, 233 healthcare workers responded to an online survey to test the impact of demographic variables, COVID-19 exposure, and psychological
resources in determining stress and burnout during the COVID-19 emergency. Frontline workers reported higher scores for stress, emotional exhaustion, and depersonalization (p < 0.001) as compared to colleagues working in units not directly serving patients with COVID-19. Mature defensive functioning was associated with resilience and personal accomplishment (r = 0.320; p < 0.001), while neurotic and immature defenses were related to perceived stress and burnout. Stress and burnout were predicted by lower age, female gender, greater exposure to COVID-19, lower resilience, and immature defensive functioning among healthcare professionals (R2 = 463; p < 0.001). Working on the frontlines of the COVID-19 pandemic appears to provoke greater stress and burnout. On the other hand, resilience and adaptive defense mechanisms predicted better adjustment. Future reaction plans should promote effective programs offering support for healthcare workers who provide direct care to patients with COVID-19.