Despite a plethora of health-related problems, access to primary healthcare is often limited for drug users (DUs). Many seek care at emergency departments and tertiary hospitals because of late presentation of illness. The costs to both DUs and the health system are such that harm reduction based healthcare centres (HRHCs) have been established in various settings and utilising a variety of models. These provide a range of medical and sometimes social services, in one, integrated, low-threshold facility, including (or closely linked with) programs such as needle syringe provision. In some countries these HRHCs are becoming an alternative healthcare system for DUs. However, the need to provide such services on a broad, public health scale, in a sustainable, cost-effective manner, raises the question as to whether such programmes should be mainstreamed. This commentary provides insights on advantages and disadvantages to mainstreaming HRHCs, and approaches and barriers to achieving this. Two approaches suggest themselves: (i) providing harm reduction services through the regular healthcare system, or (ii) more closely integrating HRHCs with mainstream services. Funding and stigma are major barriers to mainstreaming. Diverse national policies towards DUs, healthcare systems and contexts, necessitate different approaches. Because of the various barriers to mainstreaming, any steps towards mainstreaming should be taken whilst maintaining the option of continuing the current targeted harm reduction services.