- How psycho-social variables affect the degree of disease activity in patients with ulcerative colitis (UC) or Crohn’s disease (CD) is incompletely understood. Therefore, we measured and compared the impact of psycho-social variables on the active disease state in UC and CD. One hundred and twenty-two UC and 305 CD patients with active disease completed questionnaires detailing their psychological symptoms, threatening experiences, disease-coping strategies, satisfaction with life, quality of life, and demographics. UC and CD patients were aged (mean, SD) 38.6 ± 14.0 and 45.2 ± 15.1 years, respectively. The psychological symptom index (median, IQR) was greater in UC 1.24 (0.8) than CD 0.9 (0.8), p < 0.001. UC used more emotion-focused strategies, 24.5 (5.7) than CD, 23.0 (5.7), p < 0.03; problem-focused strategies, 16.4 (4.5) vs. 15.4 (4.2), p < 0.04; and dysfunctional strategies, 23.7 (5.7) vs. 22.0 (5.0), p < 0.01. UC activity correlated with gender, age, economic status, psychological symptoms, threatening experiences, all coping strategies, satisfaction with life, and quality of life (p < 0.02–0.001). CD activity correlated with economic status, psychological symptoms, threatening experiences, dysfunctional strategies, satisfaction with life, and quality of life (p < 0.05–0.001). UC activity was predicted by psychological symptoms (9.1% variance), economic status (6.9%), problem-focused strategies (4.2%), and threatening experiences (1.3%); CD activity by threatening experiences (5% variance) and psychological symptoms (4%). In path analysis, psychological symptoms and problem-focused strategies mediated the effects of economic status, age, and threatening experiences on UC activity. In CD, the dominant pathway was threatening experiences impacting on psychological symptoms. The impact of psycho-social variables on the active disease state differs between UC and CD, thus indicating a need for specifically tailored psychotherapies.