Background and Objectives: Substance use disorders (SUDs) have negative impacts on an entire family system and each family member may be at risk to develop a “codependency” on their SUD loved-one. Research has demonstrated that SUDs in the family environment associate with altered brain functioning of family members; however, research has not examined specific associations between codependency and brain functioning. Methods: Prefrontal cortex (PFC) activation of family members (n = 38) was assessed using functional near-infrared spectroscopy as they viewed images of a SUD loved-one (experimental group; n = 26) or of a “target family member” (control group; n = 12). Correlations between PFC activation and codependency were examined. Results: A significant negative association was found between codependency and left dorsomedial PFC activation in response to images of a loved-one with a SUD. This association was significantly larger than that found in the control group in response to a target family member, and that found in response to other affective images. Discussion and Conclusions: The left dorsomedial PFC is associated with executive functioning during responses to emotional and social situations. Findings may suggest that family members experiencing codependency may be limited in effectively responding to their SUD loved-one, and highlight the importance of systemic treatment and family member recovery. Scientific Significance: Codependency is often discussed as a learned condition and research has only recently examined brain processes of family members with a loved-one with a SUD. This research is the first to demonstrate an association between codependency and PFC functioning. (Am J Addict 2019;28:367–375).