The two most common comorbid conditions with HIV are substance use disorders and depression, and individuals with comorbid HIV, depression, and substance dependence face a more chronic and treatment-resistant course. As an example of how to adapt evidence-based approaches to a complex comorbid population, the current case study examined the integration of a combined depression and HIV medication adherence treatment. The resulting intervention, ACT HEALTHY, combines a brief behavioral activation approach specifically developed to treat depression in individuals receiving residential substance abuse treatment (LETS ACT; Daughters et al., 2008) with a brief cognitive-behavioral approach to improving HIV medication adherence (Life-Steps; Safren et al., 1999; Safren et al., 2009). The current case series demonstrates the use of ACT HEALTHY among 3 depressed HIV-positive, low-income African Americans entering residential substance abuse treatment.