The objectives of this study are as follow: (a) to document the prevalence of compassion fatigue (burnout and secondary traumatic stress) and compassion satisfaction in neonatal intensive care unit (NICU) nurses. (b) To explore the direct and indirect relationships of work stress and social support with compassion fatigue and compassion satisfaction. (c) To determine whether or not compassion satisfaction moderates the effect of work stress with compassion fatigue. The study was a cross-sectional correlational cohort study of 140 NICU nurses working in 4 NICUs in New South Wales, Australia. Self-report questionnaires assessed measures of professional quality of life (compassion fatigue [burnout and secondary traumatic stress] and compassion satisfaction), work stress (role ambiguity, role conflict, and role overload) and perceived social support (reassurance of worth, social integration, opportunity for nurturance, and intimacy). Work stress predicted compassion fatigue and compassion satisfaction. Role conflict and role overload were individual predictors of compassion fatigue and role ambiguity was an individual predictor of compassion satisfaction. Social support controlled for work stress predicted burnout and compassion satisfaction, but did not predict secondary traumatic stress. Intimacy-based social support was an individual predictor of burnout and compassion satisfaction, and reassurance of worth was an individual predictor of burnout. Social support mediated the effect of work stress with compassion satisfaction and moderated the effect of work stress with secondary traumatic stress. Compassion satisfaction did not moderate the relationship of work stress with compassion fatigue. Work stress and perceived social support had important direct and indirect relationships with compassion fatigue and compassion satisfaction in NICU nurses.