OBJECTIVE To assess whether systemic inflammatory response syndrome is associated with morbidity and mortality in ST-elevation myocardial infarction. METHODS Secondary analysis of multicenter randomized controlled trials. METHODS Complement and reduction of infarct size after angioplasty or lytics project patients (n=1,903) with ST-elevation myocardial infarction undergoing fibrinolysis or mechanical reperfusion. METHODS None. RESULTS The prevalence of systemic inflammatory response syndrome was described in the 1,186 patients (64.4%) with data available for all systemic inflammatory response syndrome criteria. Using multiple imputations for the 1,843 patients (96.8%) with available endpoints, we compared the 90-day prevalence of death, shock, heart failure, or stroke between patients with and without systemic inflammatory response syndrome at presentation and at 24 hours post admission. Systemic inflammatory response syndrome was defined as ≥2 of 1) heart rate>90 beats/min, 2) respiratory rate>20 breaths/min, 3) body temperature>38 or <36°C, or 4) leukocyte count>12 or<4×10/L. At presentation, 25.0% of patients met systemic inflammatory response syndrome criteria; at 24 hours, 8.1% of patients met systemic inflammatory response syndrome criteria. The primary outcome was more frequent among patients with systemic inflammatory response syndrome at presentation (31.0% vs 16.7%; adjusted hazard ratio, 1.78 [95% CI, 1.35-2.34]; p<0.001) and at 24 hours (36.7% vs 11.1%; adjusted hazard ratio, 2.84 [95% CI, 2.03-3.97]; p<0.001). Mortality at 90 days was also higher among patients with systemic inflammatory response syndrome at either time point. Each additional systemic inflammatory response syndrome criterion was independently associated with 90-day outcomes at the time of presentation (adjusted hazard ratio, 1.41 per systemic inflammatory response syndrome criteria [95% CI, 1.24-1.61]; p<0.001) and at 24 hours (adjusted hazard ratio, 1.72 per systemic inflammatory response syndrome criteria [95% CI, 1.47-2.01]; p<0.001). CONCLUSIONS The diagnosis of systemic inflammatory response syndrome and the cumulative number of systemic inflammatory response syndrome criteria were independently associated with 90-day clinical outcomes in a population of patients with ST-elevation myocardial infarction. The independent association of this simple composite measure of the inflammatory response with outcomes underscores the importance of the clinical inflammatory response in ST-elevation myocardial infarction.