Background: Nursing professionals are exposed to stressful situations arising from the work context that may affect health-related quality of life (HRQoL). The objective of this study was to analyse the relationship between sociodemographic and work-related variables regarding HRQoL in nursing professionals. Methods: A multi-centre, cross-sectional descriptive design was used. The participants consisted 1521 nurses working in healthcare centres, in both primary care and hospital care, in the eight provinces of the Andalusian Public Health System (APHS), Spain. Sociodemographic and work-related variables were analysed: Compassion fatigue, compassion satisfaction and burnout were measured using the professional quality of life questionnaire (ProQOL), and HRQoL was measured using the SF-12 health questionnaire. Results: Compassion fatigue, burnou, and, to a lesser extent, compassion satisfaction significantly influence the physical and mental components of HRQoL. The simple regression analysis showed that burnout and compassion fatigue were significantly associated with the mental component of HRQoL. Gender influenced the mental component of HRQoL. The rest of the sociodemographic and work-related variables were not significantly related to HRQoL. Conclusion: Work-related stress and repeated contact with situations of suffering influence HRQoL. Health systems must implement programmes to increase the emotional well-being of workers.