Antiretroviral drugs are associated with both short-term and long-term adverse events. Like other HIV drugs, protease inhibitors (PIs) may affect metabolic processes influencing body shape and body tissue composition, appearance, bone integrity, and cardiovascular status. However, numerous confounding variables including age, cigarette smoking, body mass index (BMI), duration of HIV infection, degree of immunodeficiency, concomitant antiretroviral agents, extent of previous treatment, and duration of treatment all blur the relationship between PI use and adverse events. Recent data suggest that the early PIs appear to have greater effects on such surrogate markers of disease risk as insulin resistance and cholesterol and triglyceride levels than the recently developed PIs. These data also suggest that evaluation of PIs as a class should be reconsidered and that it is probably not appropriate to extrapolate safety data obtained from individuals treated with first-generation agents in the era of potent combination antiretroviral therapy to those treated with recently developed PIs. Because PIs remain a critical component of successful antiretroviral therapy, evaluation of potential long-term complications with prolonged PI use is essential, as is delineation of the significant differences in safety profiles among individual PIs.