To explore the relationships of core self-evaluations of personality (self-esteem, generalized self-efficacy, emotional stability, and internal locus of control), the five-factor model personality traits (neuroticism, agreeableness, extraversion, conscientiousness, and openness), and positive and negative affect with neonatal nurses' professional quality of life (burnout, secondary traumatic stress, and compassion satisfaction). Cross-sectional cohort study. Four Level 3-4 NICUs in New South Wales, Australia. One hundred forty-two (35%) of 405 eligible neonatal nurses. Online self-report measures of personality traits, positive and negative affect, and professional quality of life. Core self-evaluations explained 33%, 21%, and 26% of the variance in burnout, secondary traumatic stress, and compassion satisfaction, respectively. After controlling for core self-evaluations, agreeableness, neuroticism, and extraversion contributed to the respective variances in burnout, secondary traumatic stress, and compassion satisfaction. After controlling for core self-evaluations and the five-factor model personality traits, positive affect contributed to the variance in burnout and compassion satisfaction, whereas negative affect contributed to the variance in secondary traumatic stress. No five-factor model personality trait contributed to the variance in professional quality of life in the final regression models. Positive affect mediated the effect of core self-evaluations on burnout and compassion satisfaction, whereas negative affect mediated the effect of core self-evaluations on secondary traumatic stress. Neonatal nurses should be aware of and accept responsibility for personality traits and moods that benefit or detract from their professional quality of life. NICU nurse managers should ensure that neonatal nurses have ready access to psychological support services.