This study assesses the effects of invasive procedures, hemostatic and clinical variables, and doses of recombinant tissue plasminogen activator (t-PA) on hemorrhagic events in the thrombolysis in myocardial ischemia (TIMI), phase 1B clinical trial (n = 1,425). Patients seen within 24 hours of the onset of ischemic chest pain at rest were randomized using a 2 x 2 factorial design for comparison of: (1) t-PA versus placebo as initial therapy, and (2) an early invasive (coronary arteriography with percutaneous angioplasty, if feasible) versus an early conservative strategy (coronary arteriography followed by revascularization if initial medical therapy failed). All patients received conventional medication for acute ischemic syndromes, including heparin, aspirin, beta blockers, nitrates, and calcium antagonists. The total dose of t-PA or placebo was 0.8 mg/kg, up to a maximum dose of 80 mg. In patients treated with t-PA, major and minor hemorrhagic events were more common than among those assigned to placebo (p < 0.001). Patients assigned to the invasive strategy arm had a higher hemorrhagic event rate than the noninvasive strategy, although the difference was not significant (p = 0.026). Patients > 75 years of age had higher intracranial hemorrhage rates than those < 75 years of age (6.7% vs 0.2%, respectively, p = 0.01). Major hemorrhagic events were more common in patients with higher heparin levels (p < 0.001), higher peak D-dimer levels (p = 0.007), and lower nadir fibrinogen levels (p = 0.005). Thus, increased morbidity due to hemorrhagic complications is associated with the use of t-PA, increased age, and selected hemostatic measures. Comparison to TIMI II demonstrates a significant association between the dose of t-PA and hemorrhagic complications.