To investigate the circadian pattern of acute myocardial infarction (MI) in a large international patient population, the time of day of the onset of symptoms was prospectively determined in 12,163 consecutive patients randomized in the ISIS-2 Trial (Second International Study of Infarct Survival). Overall, there was a marked circadian variation (P less than 0.001) in the incidence of MI characterized by a sharp increase from 0600 h to 0800 h, with a peak period from 0800 h to 1100 h followed by a gradual decline from 1100 h to 1800 h. During the evening and night there was a steady trough, with no evidence of a second peak. Although there was some scatter, this circadian pattern was similar among patients of five different geographic regions on three continents and in various subcategories of patients defined with respect to age, gender, previous MI, and aspirin intake prior to MI. The circadian pattern of diabetics, however, was different compared with non-diabetics (P less than 0.005, adjusted less than 0.01), and it demonstrated no significant variation. This increased morning incidence of MI indicates specific triggering mechanisms that are particularly likely to occur during, or just before, that time of day. Further investigation of physiological changes during the day is needed to identify any such triggers of MI and so perhaps to aid in improving preventive strategies of the disease.