Objectives. To determine how harm reduction should be applied in low-resource countries such as Vietnam by exploring the perspectives of people who use drugs (PWUD), health care professionals, and policymakers regarding methadone treatment and harm reduction strategies. Methods. We conducted 2 qualitative studies in Vietnam between 2016 and 2021. We interviewed 62 PWUD and 22 experts in drug policy development and drug treatment programs, conducted observations at methadone clinics and harm reduction program meetings, and analyzed drug policy documents. Results. PWUD considered methadone treatment only as a transition to a drug-free life. Policymakers deemed harm reduction ineffective and continued to enforce arrest and incarceration of PWUD. Drug intervention programs are not yet geared to providing specialized services. Effective communication strategies and information on evidence-based harm reduction models are inadequate to help policymakers make the right decisions. Conclusions. Harm reduction principles have not been fully adopted in Vietnam. A harm reduction strategy based on a more humanistic approach that goes beyond a biomedicalized approach is urgently needed in Vietnam and other countries in the Global South. (Am J Public Health. 2022;112(S2):S182-S190. https://doi.org/10.2105/AJPH.2022.306764).