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Chapter 3 50 Abstract Introduction Irritable Bowel Syndrome (IBS) is a brain-gut-disorder, of which the natural course varies between patients and is difficult to predict. This study aimed to evaluate symptom evolution over a five-year follow-up period and to identify baseline predictors for symptom severity and quality of life (QoL) at follow-up. Methods Maastricht IBS Cohort participants completed questionnaires upon inclusion regarding demographics and lifestyle, gastrointestinal (GI) symptoms, anxiety and depression, and QoL. The same questionnaires, in addition to others, were completed after five years. Rome criteria were confirmed face-to-face at initial enrollment and through telephonic interviews at follow-up. Results At a mean follow-up of 4.7 years, 379 patients were approached of whom 203 (53.7%) responded. Of these, 161 were reached by telephone and analyzed; 49 (30.4%) did not fulfill the Rome III criteria at follow-up and had lower levels of GI symptoms and GI- specific anxiety compared to those remaining Rome III-positive ( P <0.001). However, Rome III-negative patients had comparable levels of QoL and life satisfaction, comorbid anxiety and depression, work absenteeism and impaired productivity. No baseline predictors were found for being Rome III-positive or -negative. However, greater age and lower baseline physical QoL predicted lower physical QoL at follow-up ( P <0.005 and P <0.01, respectively), while lower baseline mental QoL predicted lower mental QoL at follow-up ( P =0.005). Additionally, higher anxiety and depression scores at follow-up were associated with lower QoL and life satisfaction at follow-up ( P <0.001). Conclusions Long-term QoL and general well-being might depend on concurrent psychological symptoms, rather than GI symptom improvement.