This study examines the association between time to treatment with thrombolytic therapy and hospital outcomes in patients with acute myocardial infarction (AMI) enrolled in a national registry. A total of 71,253 patients hospitalized with AMI from June 1994 to July 1996 who received tissue plasminogen activator (t-PA) therapy in 1,474 United States hospitals were studied. In this study sample, approximately 39% of patients presented to participating hospitals within 2 hours of acute symptom onset and received t-PA; 36% were treated within 2.1 to 4 hours, 12% between 4.1 to 6 hours, and the remaining 13% thereafter. After controlling for potentially confounding factors, in-hospital death rates increased progressively with increasing delays in time of administration of t-PA. The lowest risk for dying during acute hospitalization was seen for those treated with t-PA within 2 hours of acute symptoms. No significant association was seen between time of administration of t-PA and in-hospital risk of recurrent AMI, myocardial ischemia, cardiogenic shock, major bleeding episodes, or stroke and/or intracranial bleeding. The incidence of sustained ventricular arrhythmias declined with progressively longer time to administration of t-PA. The results of this multihospital observational study suggest that patients with AMI treated earlier with t-PA are significantly more likely to survive the acute hospitalization than patients treated later. These data reinforce the benefits to be gained by treatment with t-PA as soon as possible following the onset of acute ischemic symptoms, and for community-wide efforts to reduce the duration of prehospital delay in patients with acute coronary disease.