Background Observational data suggest that the diffuse inflammatory nature of coronary disease may be expressed by the presence of unstable coronary lesions in multiple vessels in patients with acute myocardial infarction. The aim of our study was to investigate the existence of complex lesions in nonculprit vessels in patients with ST-elevation myocardial infarction and to assess their clinical and functional significance. Methods We evaluated 974 non-infarct-related arteries (nlRAs) in 439 patients presenting within 6 hours of acute ST-elevation myocardial infarction. Coronary angiograms and electrocardiograms (ECGs) were obtained 60 minutes after fibrinolysis and systematically analyzed in core angiographic and ECG laboratories. Complex lesions in nlRA were identified according to prior criteria, that is, stenosis > 50% with one of the following: overhanging edges, markedly irregular borders, ulceration, or thrombus. Results Complex lesions were identified in 85 (8.7%) of 974 nlRAs. Seventy-three (16.7%) of 439 patients had at least 1 complex lesion in a nlRA, with 10 of the 73 patients having > 1 nlRA affected. There were no differences in baseline total ST deviation on the qualifying ECG between patients with or without nlRA complex lesions. TIN 3 flow in nlRAs occurred less frequently in vessels with complex lesions (50.8% vs 81.5%, P <.001), a difference maintained when nlRAs with stenosis between 50% and 99% were analyzed (P <.006). Patients with nlRA complex lesions had a higher inhospital incidence of congestive heart failure (16.4% vs 6.3%, P =.007) and a trend toward more recurrent ischemia (13.7% vs 7.4%, P =.102). Conclusion These findings provide new evidence supportive of the concept that active coronary lesions occur simultaneously in > 1 vessel, while also attesting to their functional and clinical significance.