Pain is a common and debilitating symptom of human immunodeficiency virus (HIV) disease, although it is often underestimated and undertreated, especially in HIV-infected intravenous drug users. It is more likely to occur in the later stages of the HIV disease, where it assumes particular significance, especially in terminally ill patients. However, its successful management is possible, though the goal of effective therapy is hampered by the side effects of highly active antiretroviral therapy and drug-drug interactions. In order to appraise these issues, a search in MEDLINE database was conducted. Book reviews and a search on relevant Web sites were also included. Treatment of HIV is itself very complex and becomes even more difficult when palliative therapy is added. Protease inhibitors, mainly ritonavir, and nonnucleoside reverse transcriptase inhibitors have higher interaction potential, due to their inducer or inhibitory actions on cytochrome P450, posing a risk when coadministered with palliative treatments; so, better outcomes can be achieved with knowledge of pharmacological aspects.