- Background: While the medical causes for exacerbation of Inflammatory Bowel Disease (IBD) are well known, the impact of psycho-social variables on the activity of Crohn's disease (CD) and ulcerative colitis (UC) are poorly understood. We determined the impact of psycho-social variables in active CD and UC. Methods: Our ongoing nation-wide psycho-social research in IBD has generated data on 818 patients. UC patients with Simple Clinical Colitis Activity Index >3 and CD patients with Harvey-Bradshaw Index >5 were entered in a cross-sectional study. Patients completed demographics, economic status (ES), medical history, and six psychological questionnaires: Brief Symptom Inventory (GSI, psychological stress measure), List of Threatening Experiences Questionnaire (LTE, exposure to major stress events), Brief COPE Inventory (coping strategies), Satisfaction with Life Scale (SWLS), SF-36 (generic health-related quality-of-life measure yielding Physical Health and Mental Health scores). Data are means (SD) or medians (IQR). Results: The cohort comprised 122 UC patients (age 38.6 (14.0) years, 60.0% women, disease duration 8.0 (3.0–14.0) years, 40.5% smokers) and 305 CD patients (age 45.2 (15.1) years, 60.1% women, disease duration 9.0 (4.0–16.0) years, 2.6% smokers). Psychological scores for UC vs. CD were: GSI 1.24 (0.8) vs. 0.9 (0.8) p<0.001, LTE 2.0 (1.0–4.0) vs. 1.5 (0–3.0), COPE Emotion-focused-strategies 24.5 (5.7) vs. 23.0 (5.7) p<0.03, COPE Planning-focused-strategies 16.4 (4.5) vs. 15.4 (4.2) p<0.04, COPE Dysfunctional-strategies 23.7 (5.7) vs. 22.0 (5.0) p<0.01, SWLS 20.1 (8.0) vs. 21.0 (8.0), SF-36-Physical 37.8 (29.2–44.6) vs. 38.5 (32.4–46.1), SF-36-Mental 37.8 (30.0–45.6) vs. 33.0 (26.6–44.6). ES was moderate (3 on scale 1–5) in UC and CD. UC disease activity was significantly associated with female gender, age, ES, GSI, LTE, all COPE strategies, SWLS and both SF-36 (p<0.02–0.001). CD activity was significantly associated with work status, smoking, ES, GSI, LTE, Dysfunctional COPE, SWLS and both SF-36 (p<0.05–0.001). A multiple linear regression model was created for UC (adjusted R square 0.11, model significance <0.001) and CD (0.185, <0.001). UC activity was predicted (R squared change) by GSI (9.1% of the variance), ES (6.9%), COPE Planning (4.2%), LTE (1.3%). CD activity was predicted by LTE (5%), GSI (4%), older age (1%). Conclusions: In this model, psychological stress impacted on both active UC (GSI) and active CD (LTE), whereas economic status impacted on UC only. Planning-focused coping was significant for active UC but not CD. Additional research is required to determine whether other psycho-social variables predict activity in these diseases.