The objective of this research was to analyse the quality of life of nursing professionals and its relationship with socio-demographic variables and the work context. A multi-centre, descriptive, cross-sectional design was used. Questionnaires were administered to 1521 nurses working in the Andalusian Public Health System (APHS), Spain. Professional quality of life (ProQOL v. IV) was measured, as well as several socio-demographic and work-related variables. To this end, a descriptive analysis and multiple exploratory analyses were conducted. The levels of compassion fatigue (CF) and burnout (BO) were elevated. The level of compassion satisfaction (CS) was below the estimated mean. Marital status, the healthcare setting, the area where the centre is located, and the work shift are variables associated with CF. According to the multiple linear regression model, the predicting factors for the occurrence of CF were being married, working in primary care, in urban areas, and working a morning/evening/night shift. The variables related to CS were the professional’s age, sex, marital status, the healthcare setting of the centre, the location of the centre, and the work shift. Specifically, according to the exploratory model, the factors that predicted a reduction in CS were working in primary care, in urban areas, and working a morning/evening/night shift. However, being divorced increased CS. BO was influenced only by the work shift. Nursing professionals are exposed to certain factors that may influence professional quality of life. Some of these factors are related to the work context.