Bleeding in the setting of acute coronary syndromes (ACS) has negative prognostic implications. We sought to determine the impact of different levels of on-treatment platelet reactivity (PR) to ADP on both bleeding and ischemic events in ACS patients receiving coronary stenting. PR to ADP was measured with the VerifyNow P₂Y₁₂ assay (Accumetrics, San Diego, CA) in 374 patients with ACS receiving standard dual antiplatelet therapy. Patients were stratified into three tertiles according to the increasing values of P₂Y₁₂ reaction units with the first tertile defined as low, second as medium, and third as high PR. The end points were bleeding (TIMI major or minor), ischemic end point (cardiovascular death and non-fatal myocardial infarction), and combined end point (bleeding or ischemic end point). At 30 days: low PR was associated with increased risk of bleeding as compared to medium (adjusted hazard ratio [HR] 3.50, 95% confidence intervals (CI) 1.30-9.42, p = 0.013) and high PR (HR 2.78, 95% CI 1.50-5.15, p = 0.001); high PR posed increased risk of ischemic endpoint as compared with medium PR (HR 7.26, 95% CI 1.67-31.55, p = 0.008) and a trend towards higher incidence of ischemic events was observed when compared with low PR (HR 1.51, 95% CI 0.96-2.36, p = 0.074); patients with medium PR were at significantly lower risk of combined end point as compared to those with low (HR 0.30, 95% CI 0.12-0.75, p = 0.01) and high PR (HR 0.31, 95% CI 0.12-0.77, p = 0.012). In conclusion, low PR to ADP is associated with increased hazard of bleeding and poses similar combined risk of bleeding and ischemic events as high PR. Medium PR predicts favorable net outcome in ACS patients.