Although the efficacy of glycoprotein IIb/IIIa inhibition in non-ST-elevation acute coronary syndromes is greatest in patients who undergo percutaneous coronary intervention (PCI), it was hypothesized that high-risk patients managed without PCI also benefit. The TIMI risk score was calculated for 1,570 patients randomized to tirofiban plus heparin versus heparin in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. In high-risk patients (score > or =4) treated without PCI, tirofiban reduced the risk for death, myocardial infarction, and refractory ischemia at 30 days (28.8% vs 21.9%; odds ratio [OR] 0.69, p = 0.04). This benefit was similar in magnitude as that for patients who underwent PCI (32.4% vs 22.2%; OR 0.60, p = 0.06). No benefit was evident in low-risk patients.