Our objective was to explore the relationship between psychological distress and subsequent Crohn's disease (CD) activity. Eighteen CD patients were followed prospectively for 2 years at 8- to 12-week intervals. Disease activity was assessed using the Crohn's Disease Activity Index (CDAI). Psychological distress was assessed using the following self-administered questionnaires: Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Beck Hopelessness Scale (BHS), and multiple Holmes Recent Life Changes (RLC) Questionnaires. The effects of psychological distress on current and subsequent CDAI (approximately 8–12 weeks later) were assessed using generalized estimating equations (GEE). The mean CDAI score during follow-up was 138 ± 86, with a median of 121 (range, 0 to 394). BDI scores (possible range of 0 to 63) were independently associated with CDAI scores simultaneously (β =5.64, P=0.004) and 8–12 weeks later (β =6.08, P=0.004). Higher levels of anxiety, hopelessness, and recent life changes were also suggestive of higher CDAI scores, however, their effects were generally of lesser magnitude and not independent of the influence of depressive symptoms. Levels of depressive symptoms are positively associated with future changes in CDAI. Routine psychological assessment may help to identify patients at higher risk for exacerbation.