This study was conducted to compare the efficacy of Quality of Life Therapy (QLT) on cognitive flexibility and family cohesiveness among patients with opioid substance use in experimental and control groups. Participants included 56 male outpatients with opioid substance use from Khorramabad City, Lorestan province, Iran. A demographic questionnaire, the Cognitive Flexibility Inventory (CFI; Dennis, & Vander Wal, 2010) and the Family Adaptability and Cohesion Evaluation Scale (FACES IV, Olson, 2000) were used for data collection in this study. Findings showed significant differences about the efficacy of QLT among outpatients with opioid substance abuse in experimental and control groups in cognitive flexibility and family cohesiveness during post-test and follow-up stages in this sample. The QLT was effective on increasing of cognitive flexibility and family cohesiveness among outpatients with opioid substance abuse in participants of the experimental group during post-test and follow-up stages. Clinicians and mental health professionals may use the QLT for increasing of cognitive flexibility and family cohesiveness among outpatients with opioid substance abuse.