Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.