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Harm reduction, including needle exchange and opioid substitution therapy, has been demonstrated to reduce high-risk behavior and HIV infection among injection drug users. An increasing number of countries in the Middle East, North Africa, and Asia, including those with Muslim majorities, have experienced or are at risk for HIV epidemics initiated by burgeoning injection drug use. Although use of intoxicants is expressly forbidden within Islam, the local culture impacts the interpretation of Islamic law and influences the response to drug misuse, whether punitive or therapeutic. Harm reduction programming has received varying acceptance within this global region, which may be reflected by national trends in HIV prevalence. The purpose of this paper is to examine cultural and religious response to injecting drug use and associated HIV prevalence trends in Malaysia and Iran, with possible application of lessons learned to an emerging situation in Afghanistan.