BACKGROUND: Irritable Bowel Syndrome (IBS) negatively influences mental and physical quality of life (QoL), but factors that explain this impact are still unclear. Increasing evidence has associated IBS severity, psychological distress, somatic symptoms, and gastrointestinal (GI)-specific anxiety with QoL in IBS. The aim of this study is to further explore these associations and to analyze potential mediating factors. METHOD: A total of 1017 IBS patients (69.3% female, mean age 40.6 years) who completed a QoL measure (SF-36) were included in this study. A proportion of these participants (N = 183; 72.7% female, mean age 41.7), who additionally completed psychological distress, somatic symptoms, and GI-specific anxiety measures, was included in the mediation analysis. This analysis was conducted via structural equation modelling to identify factors of importance for generic QoL, using a cross-sectional design. RESULTS: IBS patients reported lower QoL than what is observed in the general population, in particular regarding role limitations caused by health and emotional functioning, vitality, and social functioning. Female patients scored lower than male patients on most QoL dimensions. The effects of IBS severity on mental and physical QoL were mediated by GI-specific anxiety. In addition to GI-specific anxiety, depressive symptoms were also of importance for mental QoL, and somatic symptom severity for physical QoL. CONCLUSION: QoL is reduced in patients with IBS and GI-specific anxiety, depressive symptoms, and somatic complaints are particularly important for this outcome. Future trials should test the efficacy of psychological interventions specifically targeting these factors in improving QoL in IBS.