Background: Behcet's disease (BD) is a chronic, systemic inflammatory disease characterized with higher prevalence of psychiatric disorders, particularly major depression. This study aimed to determine the relationship between the psychological coping strategies with the disease and depression, anxiety, quality of life and disease activity in patients with BD. Methods: Fifty Behcet's patients and 38 control subjects were compared by using Behcet's disease current activity form (BDCAF), quality of life instrument (QOL), structured clinical interview for DSM-IV axis I disorders (SCID-I), ways of coping questionnaire (WCQ), Beck depression inventory (BDI), and Beck anxiety inventory (BAI). Results: In terms of coping, self-controlling and positive reappraisal scores were lower in BD patients than controls while escape-avoidance was negatively correlated with age in patients. Confrontive coping, accepting responsibility, and escape-avoidance scores were positively correlated with BDI and BAI. Confrontive coping, accepting responsibility, and planful problem solving were positively correlated with QOL score. Multiple linear regression analysis indicated that confrontative coping was the major predictive factor for QOL and BDI scores. Conclusions: Excessive use of confrontive coping, accepting responsibility, and escape-avoidance strategies seems to increase depression and anxiety in Behcet's patients. Besides, among those strategies, confrontive coping is significantly associated with depression and quality of life in BD patients that should be considered in therapeutic approaches. Our results highlighted that Behcet's patients have different coping strategies than healthy controls that may impair the psychological adjustment process.