ABSTRACT Introduction Depression and anxiety are among the most prevalent mental health conditions in Brazil. Both are associated with poor quality of life (HRQoL) and challenges in disease management for chronic illnesses, including Behçet’s disease (BD). This study aimed to evaluate depression, anxiety, and HRQoL in BD patients from a non-endemic area. Research design and methods This case-control study included adult BD patients from Brazilian tertiary center and healthy controls (HC). All patients fulfilled the ISG and ICBD diagnostic criteria. Depression, anxiety and quality of life were assessed using BDI, HADS, SF-36, and physical capacity with the HAQ. Results We enrolled 58 BD patients (60% female, median age 48.5) and 96 HC (74% female, median age 40.5). High rates of depression and anxiety were observed in BD patients, correlating with disease activity, younger age, absence of a partner, shorter disease duration, and lower income. BD patients showed significant HRQoL restrictions, particularly in physical and emotional roles, compared to HC. Longer disease duration correlated with better HRQoL. Conclusion High rates of depression and anxiety were observed in BD patients, negatively impacting HRQoL, particularly in those with higher disease activity. Further study and clinical attention are warranted to enhance patient care and outcomes.