Opioid and cocaine use epidemics continue to be substantial in the United States and intersect with the HIV epidemic. Antiretroviral medication (ARV) adherence is critical for optimum HIV outcomes. While previous research explored harm reduction strategies to prevent HIV spread for people who use drugs (PWUD), little is known about strategies used by PWUD living with HIV to maintain ARV adherence. We explored whether PWUD modify their drug use explicitly to maintain ARV adherence, and identified factors associated with this process. We conducted 23 semi-structured interviews. Data were analyzed using a modified framework analysis approach. Participants had a mean age of 54 years and were predominantly male (70%) and non-Hispanic black (65%). Most described periods of being able to adhere to ARVs while still using drugs, difficulty adhering to ARVs while using drugs, and abstinence/near abstinence from drug use. In exploring factors that influenced changes in drug use and ARV adherence behaviors, we noted consistent acknowledgment of the roles of family, partners, or providers. PWUD living with HIV often modify their drug use to improve ARV adherence. Providers caring for this population might consider family or group education models to encourage harm reduction to improve outcomes.