Background Rehabilitation programs targeted to patients with substance use disorder (SUD) following successful detoxification constitute a global public health concern. This study aimed to examine the effectiveness of a combined pharmacotherapy/cognitive behavior therapy (CBT) model through assessing abstinence/relapse rate and quality of life (QOL) in a sample of patients with SUD. Indeed, we aimed to identify the relapse predictors. Results The relapse rate in the inpatient group was 45.33%, compared to 56% in the outpatient group. Multivariate analysis revealed that patients with educational levels less than secondary school, rural residency, being single or divorced, having cravings lasting for 6 weeks from detoxification, legal history, presence of borderline, antisocial and multiple personality disorder could predict relapse in patients with SUD. Moreover, there was a statistically significant difference between the legal, substance, and social domains of ASI (X2= 12.525, p=0.014; X2= 12.525, p=0.023; and X2= 6.335, p=0.042 respectively) and the majority of QOL domains and relapse. Conclusions Socio-demographic data, legal history, craving, and presence of co-morbid personality disorders along with, legal, substance, and social domains of ASI might be implicated in relapse, suggesting that addiction rehabilitation programs targeting these topics would reduce the risk of relapse.