The introduction of highly active antiretroviral therapy (HAART) has significantly modified the course of HIV disease, with longer survival and improved quality of life of HIV-infected subjects. However, HAART regimens, especially those including protease inhibitors (PIs) have been shown to cause in a high proportion of HIV-infected patients a metabolic syndrome that may be associated with an increased risk of cardiovascular disease (about 1.4 cardiac events per 1000 years of therapy according to the Framingham score). Metabolic features associated with somatic changes (lipodystrophy/lipoatrophy) include dyslipidemia (about 70% of patients), insulin resistance (elevated C-peptide and insulin), type 2 diabetes mellitus (8%–10% of the patients), hypertension (up to 75% of patients), coagulation abnormalities (25% of patients), lactic acidemia, and elevated hepatic transaminases (nonalcoholic steatohepatitis). HAART-associated metabolic syndrome is an increasingly recognized clinical entity. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the cardiovascular risk in patients under HAART. A careful stratification of the cardiovascular risk and cardiovascular monitoring of patients under HAART is needed according to the most recent clinical guidelines.