Patients with inflammatory bowel disease (IBD) often report symptoms of anxiety and depression as well as impaired quality of life (QoL). To date, there are few studies on the effect of psychotherapy on psychological functioning and clinical outcome in patients with IBD. The aim of this prospective, randomized, controlled study was to investigate the effect of a brief psychotherapeutic intervention on psychological distress, QoL, sexual functioning, and inflammation and disease activity indices in patients with IBD. Participants were randomized to receive either group cognitive behavioral therapy or treatment as usual (controls) and were assessed at baseline and after six months using psychometric instruments to assess psychological distress, QoL, and sexual functioning. In addition, laboratory measurements, including levels of C-reactive protein (CRP), cytokines and calprotectin, and calculations of disease activity indices were performed during the two study periods. 80 participants took part in the study. Patients who received psychotherapy reported a significant decrease in anxiety and depression symptoms, a significant improvement in physical functioning, general health, vitality, social functioning and mental health, a decrease in physical pain and a decrease in role limitations caused by emotional problems. CRP levels and the Crohn's disease activity index (CDAI) also decreased significantly at follow-up compared to controls. Group cognitive behavioral therapy is proving to be an important component of holistic care for IBD patients, as it can significantly improve not only patients' psychosocial functioning but also their clinical course by inhibiting inflammation and reducing disease activity.