Despite improving strategies for control of risk factors, progression of atherosclerosis may lead to recurrent cardiac events related to a lesion other than that treated with initial percutaneous coronary intervention (PCI) after ST-elevation myocardial infarction (STEMI). Of 1,007 consecutive patients undergoing primary or rescue PCI for STEMI, 897 who were discharged alive were followed for up to 3 years. Those who underwent nontarget lesion revascularization (non-TLR) were compared with those who did not. Those who underwent a second procedure were followed for an additional 1 year. Altogether, 94 patients (10.5%) required a non-TLR. The median time from the first to the second PCI was 396 days (interquartile range 131 to 533). Subsequent PCI was required for non-STEMI in 46.1% and STEMI in 9.7% of cases. Independent predictors of need for non-TLR were diabetes mellitus, history of coronary bypass surgery, or peripheral vascular disease. By 1 year after the second PCI, 9 patients (9.6%) died, 4 (4.3%) had sustained MI, and 4 (4.3%) had TLR. One of these major adverse events had occurred in 17 (18%). In conclusion, after STEMI, nearly 10% of patients will develop an event that requires subsequent PCI to an unrelated lesion. Patients with diabetes mellitus, history of coronary bypass surgery, or peripheral vascular disease are at increased risk for this event. Aggressive preventive and medical management should be applied to this population for prevention of these subsequent events.