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Background: Inflammatory bowel diseases (IBD) affect patients' health-related quality of life (HRQoL) and are associated with higher levels of anxiety and depression. We aimed to investigate whether illness perceptions and coping strategies were associated with mental adjustment (depression and anxiety) and HRQoL in IBD.Methods: Patients were prospectively recruited at a tertiary IBD Center. Self-administered questionnaires evaluating patients' demographics, illness perceptions, coping strategies, catastrophization, HRQoL, depression and anxiety were completed. Analysis was performed using Pearson's product moment correlation coefficient, hierarchical regression and structural equations modeling.Results: IBD patients (n=156, 117 Crohn's disease, 30 ulcerative colitis, and 9 IBD-undetermined), 49% females, mean age 41.6±14.79 (19–77) years, mean disease duration 12±9.42 (1–37) years were included. Severe anxiety was reported in 30% (n=45) and 23% reported severe depression (n=33). Mean HRQoL was 5.12±1.09.Illness perceptions that had an association with all or most HRQoL subscales were: Perception of the treatment as effective (β=0.28, p<0.01), perception of understanding the disease (β=0.28, p<0.01), and the perception of the disease as cyclical, which was negatively correlated to HRQoL (β=−0.22, p<0.05). Coping strategies that were more beneficial to IBD are characterized by acceptance of IBD and its challenges while trying to go on with life and engage in meaningful activities. Coping strategies that indicate inability to accept the disease, giving up, or using distractions, were all related to lower HRQoL and higher levels of depression and anxiety. Two coping strategies mediated the association between illness perceptions and HRQoL: “comparison to others” and “activities engagement”.Gender, education level and coping strategies predicted 73% of the explained variance in HRQoL of these patients.Conclusions: Illness perceptions and coping strategies may promote patients' HRQoL and mental state. Therefore, modifying illness perceptions and coping strategies using psychosocial interventions may contribute to HRQoL in patients with IBD.