Substance use disorders cause significant neurological damage, cognitive impairment, and maladaptive behaviors that negatively affect a person's quality of life. The purpose of this study was to explore the effect gender and primary drugs have on locus of control. Generalized expectancy theory helped to explain the behavior of patients diagnosed with substance use disorders and their inability to control ongoing drug use. The research question focused on to what extent drug-related locus of control scores differ by primary drug (narcotic vs. stimulant), gender (male vs. female), and their interaction. Data measuring locus of control from 553 participants provided a subset of 410 participants who identified narcotics or stimulants as their primary drug. A 2x2 full factorial ANOVA was conducted. The results of this study indicated there is a significant interaction between primary drug use and gender. The results could have positive social change implications for the addiction field because of the value of understanding the interdependency of internal-external thought processes related to drug use, the ability to change stigma associated with addiction and gender, and the value of understanding the need for individualized treatment as locus of control shifts from external to internal. It is recommended that the drug-related locus of control instrument become part of treatment protocol along with evidence-based interventions.