Gender has been associated with substance use disorders (SUD). However, there are few studies that have evaluated gender differences in a global and a standardized way, and with a large sample of patients with SUD. Our goal is to analyze the role of gender in addiction severity throughout multiple life domains, using the Addiction Severity Index-6 (ASI-6). A naturalistic, multicenter and prospective study was conducted. A total of 221 patients with SUD (80.1% men) were interviewed with the ASI-6. Our results indicate that the Recent Summary Scores (RSSs) of men and women are similar, with the exception of Psychiatric and Partner- Problems, where women showed higher severity (p = .017 and p = .013, respectively). Statistically significant gender differences were found in certain aspects of the ASI-6 domains: men have more problems of physical health, legal issues, and alcohol and other substance use; and woman score higher in problems of mental health, social network, subjective evaluations of SUD consequences, and treatment needs. These results should be taken into account to improve the identification, prevention, and treatment of SUD.