The South-East Asia Region is home to between 3.4 and 5.6 million injecting drug users. A large proportion of them resort to unsafe injecting practices such as sharing of needles and syringes. This has led to the rapid and large-scale transmission of HIV and hepatitis C in this population and their partners. In order to prevent new infections, countries need to urgently expand the implementation of evidence-based drug treatment interventions. Opioid substitution therapy (OST) is the most useful and cost-effective intervention for managing opioid dependence and reducing the harms associated with it. OST is now available in India, Thailand, Indonesia and Nepal, and will soon be introduced in the Maldives and Bangladesh. These practical guidelines aim to assist physicians and drug treatment professionals in establishing and delivering evidence-based, good quality, effective OST services in South-East Asia.