Tissue plasminogen activator (tPA) is emerging as an important risk factor for coronary heart disease, but the association between tPA concentration and mortality in acute myocardial infarction (AMI) remains uncertain. We studied the relationship between tPA antigen level on admission and 30-day mortality in 226 consecutive patients with AMI undergoing primary angioplasty. Death within 30 days occurred in 13 patients (5.7%). The concentration of tPA was significantly higher among the 13 patients who died than among the 213 who survived (26.5+/-16.3 versus 12.5+/-8.5 ng/mL, p<0.001). Compared with those in the lowest quartile (<9 ng/mL), patients in the highest quartile (>16 ng/mL) had a relative risk of subsequent death of 13.1 (p=0.014). In a Cox regression model, a tPA concentration >19 ng/mL was independently associated with mortality (HR 12.1, 95% CI, 1.9-76.7, p=0.001). This cutoff value had a 76.9% sensitivity and an 85.9% specificity for predicting 30-day mortality. tPA concentration was also higher in patients with severe heart failure (20.9+/-14.2 ng/mL versus 11.7+/-7.5 ng/mL, p=0.001) or ventricular tachyarrhythmia (24.3+/-13.9 ng/mL versus 12.2+/-8.4 ng/mL, p=0.001). In conclusions, elevated tPA antigen at initial presentation in patients with AMI was associated with higher short-term risk of death, suggesting that tPA may be a useful prognostic biomarker for the early risk stratification of these patients.