Background: The COMplement inhibition in Myocardial infarction treated with Angioplasty(COMMA) trial previously demonstrated an unexpected dose-dependent reduction in 90-day mortality after bolus/infusion of pexelizumab despite no reduction in the primary end point of myocardial infarction(MI) size. We examined whether the mortality benefit was related to established modulators of clinical benefit such as baseline demographics, time to treatment from symptom onset, myocardial perfusion post-percutan-eous coronary intervention(PCI), and extent of ST resolution. Methods and Results: Eight hundred fourteen patients were randomized into 3 groups;(1) placebo,(2) pexelizumab bolus 2.0 mg/kg and placebo infusion for 20 hours, and(3) pexelizumab bolus 2.0 and 0.05 mg/kg per hour infusion for 20 hours commencing 4 hours after the bolus. Subjects presented with ST elevation MI within 6 hours of symptom onset and underwent PCI, creatine kinase(CK), and CK-MB measurements taken sequentially to define CK-MB area under the curve(AUC) and sequential ECG’s defined ST resolution and QRS infarct size. Whereas mortality for both placebo and bolus pexelizumab groups rose during later time after presentation, it remained low and did not change appreciably during the 6-hour randomization window when patients received pexelizumab bolus infusion. Amplification of the mortality benefit was evident in patients with the highest quartile of hemodynamic compromise, that is, heart rate ≥90 beat/min and systolic blood pressure ≤118 mm Hg(3.2%vs 11.3%P=.004). A significant interaction between treatment assignment and hemodynamic status(P=.013) existed after adjusting for age, race, and MI location. Clinical benefit was not related to infarct size, extent of ST elevation, or evidence of angiographic or electrocardiographic reperfusion. Conclusions: These data raise the possibility that the clinical benefit of pexelizumab is mediated through novel pathways such as reduction in apoptosis or other mechanisms. Background: The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial originally demonstrated an unexpected dose-dependent reduction in 90-day mortality after bolus / infusion of pexelizumab with no reduction in the primary end point of myocardial infarction (MI) size. We examined whether the mortality benefit was related to established modulators of clinical benefit such as baseline demographics, time to treatment from symptom onset, myocardial perfusion post-percutan-eous coronary intervention (PCI), and extent of ST resolution. Methods and Results: Eight hundred fourteen patients were randomized into 3 groups; (1) placebo, (2) pexelizumab bolus 2.0 mg / kg and placebo infusion for 20 hours, and (3) pexelizumab bolus 2.0 and 0.05 mg / kg per hour infusion for 20 hours commencing 4 hours after the bolus. Subjects presented with ST elevation MI within 6 hours of symptom onset and underwent PCI, creatine kinase (CK), and CK-MB measurements taken sequentially to def ine CK-MB area under the curve (AUC) and sequential ECG’s defined ST resolution and QRS infarct size. Whereas mortality for both placebo and bolus pexelizumab groups rose during later time after presentation, it remained low and did not change appreciably during the 6- hour randomization window when patients received pexelizumab bolus infusion. Amplification of the mortality benefit was evident in patients with the highest quartile of hemodynamic compromise, that is, heart rate ≥90 beat / min and systolic blood pressure ≤118 mm Hg (3.2% vs 11.3 % P = .004). A significant interaction between treatment assignment and hemodynamic status (P = .013) existed after adjusting for age, race, and MI location. Clinical benefit was not related to infarct size, extent of ST elevation, or evidence of angiographic or electrocardiographic reperfusion. Conclusions: These data raise the possibility that the clinical benefit of pexelizumab is mediated through novel pathways such as reduction in apoptosis or other mechanisms.