Patients with HIV who are receiving antiretroviral (ARV) therapy are at high risk for drug-drug interactions (DDIs), which can significantly impact patient care and represent a substantial opportunity cost for healthcare systems. DDIs are prevalent in the developed world and in resource-poor settings, with the cost being potentially greater in the latter. Although practically unavoidable in HIV care, many DDIs can be better managed, reducing the risks to patients and the burden on resources. The scope for DDI management is likely to be greater in the developed world, due to the availability of new agents and second-line drugs, which allow greater flexibility of ARV regimens and co-administered drug choice. The advent of electronic prescribing and patient medication records represents an opportunity to aid the identification and management of DDIs. Searchable electronic databases of HIV drug interactions are available, which are a useful tool for HIV healthcare professionals and non-specialists for managing DDIs involving ARVs. Although general active systems that alert prescribers to DDIs currently exist, there is an indication for the development of specialist active databases to be incorporated into electronic prescribing or dispensing systems, with the aim of improving the quality of prescribing and the safe dispensing of the therapeutically risky drugs and complicated regimens used in HIV management.