Some studies have shown that currently available protease inhibitors (PIs) are associated with an increased risk of cardiovascular disease. We have systematically reviewed the published literature and conference abstracts for studies evaluating cardiovascular risk factors and events in patients receiving highly active antiretroviral therapy, with and without PIs. The majority of studies showed that the use of PIs was associated with increased levels of total cholesterol (36 [75%] of 48 studies), triglycerides (35 [73%] of 48 studies), and low-density lipoprotein (12 [100%] of 12 studies). PI use was often associated with morphological signs of cardiovascular disease, such as increased carotid intima thickness or atherosclerotic lesions (7 [88%] of 8 studies). Finally, 2 (67%) of 3 long-term observational studies that met our inclusion criteria demonstrated an association between use of PIs and subsequent myocardial infarction. The benefits of the currently available PIs should be balanced against the long-term risk of cardiovascular disease.