Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, acts via the flt-1 receptor and promotes endothelial activation and macrophage recruitment into atherosclerotic lesions. We investigated the relationship of PlGF with cardiovascular outcomes in a large cohort of patients presenting across the spectrum of ACS. PlGF was measured at baseline (n = 3,761) and at four-months (n = 3,369) in patients randomized to atorvastatin 80 mg or pravastatin 40 mg after ACS in the PROVE IT-TIMI 22 trial. The primary endpoint was death, myocardial infarction (MI), unstable angina, revascularization or stroke (mean follow-up 24 months). Elevated baseline PlGF was associated with a higher incidence of the primary endpoint through 2 years (Q1 vs. Q5: 18.7 vs. 29.3%, p < 0.0001). The risk of death or MI was also higher in patients with elevated baseline PlGF (Q1 vs. Q5: 7.0 vs. 11.6%, p = 0.029). Adjusting for baseline characteristics and risk factors, elevated baseline PlGF was independently associated with the risk of the primary endpoint (adjusted-HR for Q5 vs. Q1 1.45; 95% CI 1.16-1.83; p = 0.001). Elevated PlGF at four months was associated with higher risk of death or MI (Adjusted HR Q5 vs. Q1 2.79, 95% CI: 1.37-5.68; p = 0.005), and higher risk of the primary endpoint (Adjusted HR Q5 vs. Q1 1.78, 95% CI: 1.26-2.51; p = 0.001). Higher concentration of PlGF after ACS is associated with long-term risk of recurrent cardiovascular events independent of traditional risk factors. This association is present early after ACS and appears to be stronger at four months.