The objective of the study was to analyse the impact of fibromyalgia (FM) on health-related quality of life (HRQOL) and to identify clinical and psychological factors associated with the disease. A cross-sectional study was conducted with adult Portuguese women with FM. Analysed data were demographic, clinical and psychological variables and HRQOL: SF-36 and Fibromyalgia Impact Questionnaire (FIQ). The relationship between HRQOL and the other variables was made with a bivariate analysis. To assess the relative contribution of clinical and psychological variables, a series of multiple regression analyses were designed and made. The study sample consisted of 76 women with FM (49.61 ± 10.07 years). All dimensions of HRQOL were affected in FM, especially Physical Functioning, Physical Role Functioning and General Health. The mean FIQ total score was 68.59 ± 17.54, and 40 patients (53%) presented scores ≥70. Pain intensity, assessed by a 10-cm visual analogue scale (VAS), was a significant predictor of HRQOL in expressing association with FIQ and all dimensions of SF-36, except Emotional Role Functioning. Anxiety (Hospital Anxiety and Depression Scale (HADS)) was a significant predictor of the Mental Component and General Health (SF-36). Depression (HADS) was related with Vitality, Mental Health and FIQ. Emotion-focused coping was related with General Health and Emotional Role Functioning, and social support (Satisfaction with Social Support Scale (ESSS)) was related with the Social Functioning. These clinical and psychological variables explained an acceptable proportion of variability (R (2)), ranging from 31.3% on Emotional Role Functioning to 70.6% on FIQ, except for Physical Role Functioning (R (2) = 6.1). FM has a negative impact on both general and specific dimensions of HRQOL, especially the physical dimensions. Pain intensity, anxiety and depression symptoms and the emotion-focused coping are the most relevant explanatory variables of the impact of FM on HRQOL.