Opioid dependence remains one of the most severe chronic disorders, characterized by high mortality and relapse rates. According to the WHO, more than 62 million people worldwide are affected, while in Ukraine only 15–20 % of patients receive appropriate treatment. The aim of this study was to compare the effectiveness of comprehensive therapy (opioid substitution maintenance therapy combined with psychological correction and psychotherapeutic interventions) with opioid substitution monotherapy in terms of mental and behavioral symptoms and quality of life among patients with opioid dependence. A total of 150 patients were examined and allocated into the main group (n = 101) and the comparison group (n = 49). Assessment tools included SCL-90-R, HAM-A, HAM-D, the Bass–Darky aggression inventory, and the WHOQOLBREF. The intervention package in the main group comprised psychoeducation, motivational interviewing, cognitive-behavioral therapy, group and family-based interventions, social support, and skills training. Comprehensive therapy demonstrated substantially greater reductions in anxiety and depressive symptoms compared to monotherapy, as confirmed by HAM-A and HAM-D scores. According to SCL-90-R, patients in the comprehensive program exhibited a systematic decrease in psychopathological distress, including reductions in depressive and anxiety symptoms, as well as improvements in global severity indices. All WHOQOL-BREF domains improved exclusively in the main group, indicating a favorable impact of the integrated approach on daily functioning. Aggression and hostility scores (Bass–Darky) did not differ significantly between groups, suggesting lower sensitivity of these traits to short-term interventions. The findings support the superiority of a biopsychosocial treatment model, which may be considered an optimal standard of care for individuals with opioid dependence.