Objectives To study the relationship between exposure to protease inhibitor (PI) therapy and increased risk of cardiovascular events in HIV-infected patients. Methods We estimated the risk of cardiovascular disease (CVD) events with PI exposure in a cohort of HIV-infected patients using a time-dependent Cox proportional hazards model adjusting for the major CVD risk factors. Only the first CVD event for each subject was counted. Results Of a total of 7542 patients, 77% were exposed to Pls. CVD event rates were 9.8/1000 and 6.5/1000 person-years of follow-up (PYFU) in the PI-exposed and nonexposed groups, respectively (P = 0.0008). PI exposure ≥ 60 days was associated with an increased risk of CVD event [adjusted hazards ratio (HRadj) 1.71; 95% confidence interval (CI) 1.08-2.74; P = 0.03]. Results from a subgroup of patients aged between 35 and 65 years were similar (HRadj 1.90; 95% CI 1.13-3.20; P = 0.02). Other significant risk factors included smoking status, age, hypertension, diabetes mellitus and pre-existing CVD. Conclusions Patients exposed to PI therapy had an increased risk of CVD events. Clinicians should evaluate the risk of CVD when making treatment decisions for HIV-infected patients.