The comorbidity between Personality Disorders and Substance Use Disorders is well documented. Relationships between these two mental disorders are complex, and their concomitance generates poorer therapeutic prognosis and more severe psychosocial problems than either disorder alone. The purpose of this study was to compare three models of the relationship between personality disorders, substance use disorders and substance-related problems. Substance use disorder patients (n = 199) were recruited from outpatient centers for drug abuse care. The International Personality Disorder Examination Screening Questionnaire, European Addiction Severity Index and Substance Dependence Severity Scale were administered. For statistical analysis, t test, Pearson correlations and structural equation models were used. Patients with comorbidity showed more severe substance use disorder and more substance-related problems than patients without comorbidity. The three models fit well to the data, but two model with the effect mediation of severity of substance dependence between personality disorders and substance-related problems explained more variance observed. Considering the impact of personality disorders on family/social functioning, legal status and employment in these patients, integrated treatment models are needed to provide efficient care.