GISSI 3 is an open randomized population trial to assess the comparative value of two different therapeutic strategies based on nitrates and angiotensin-converting enzyme inhibition respectively versus routine treatment in improving the short- and long-term outcome of patients with acute myocardial infarction. Methodologically the protocol of this trial may be seen from two complementary points of view: (1) as the natural continuation of a successful formula (inclusion of the large majority of Italian coronary care units) which has proven capable of producing interesting experimental results with direct epidemiological and public health implications and (2) as the evolution of a strategy which was restricted mainly to coronary care units to include intensive posthospital surveillance of the recruited patients whose outcome is measured on the basis of the combined end point of mortality and severe left-ventricular damage. The pharmacological and clinical interests of comparing the effects of a nitrate-based approach (predominantly vasodilation) and a multitargeted one based on angiotensin-converting enzyme inhibition (lisinopril is the study drug) need not be emphasized. The pilot study is now completed and the main trial will commence in summer 1991 recruiting 20,000 patients with acute myocardial infarction who will be randomized within 24 h after onset of pain and followed up for 12 months. The main study will follow a 2 × 2 factorial design with four treatment groups: lisinopril alone nitrates alone combined therapy and no trial therapy.