In a study with 2 x 2 factorial design, 20,891 patients with suspected acute myocardial infarction of less than 6 h duration (12,490 from the GISSI-2 trial and 8401 recruited elsewhere) were randomly allocated to alteplase (recombinant tissue plasminogen activator, tPA) or streptokinase (SK) and to subcutaneous heparin, beginning 12 h after the start of thrombolytic therapy or no heparin. The protocol recommended that, in the absence of specific contraindications, all patients should receive aspirin and intravenous beta-blockade as soon as possible. No significant differences in hospital mortality were found between tPA and SK (8.9% versus 8.5%) or between heparin and no heparin (8.5% versus 8.9%). The incidence of major cardiac complications was also very similar in the different groups. For non-cardiac complications significant differences between the treatment groups were observed: more strokes were reported with tPA than with SK (1.3% versus 1%) while more major bleeds occurred with SK than with tPA (0.6% versus 0.9%). Subcutaneous heparin was likewise associated with an excess of major bleeds (1.0% with heparin versus 0.5% without heparin) but did not affect the incidence of stroke or reinfarction.