Advances in percutaneous coronary intervention (PCI) have reduced complications but expanded indications. We used the National Heart, Lung, and Blood Insitute Dynamic Registry to determine clinical outcomes up to 1 year after PCI in 2,839 patients with at least 1 treated complex lesion (defined as a lesion showing evidence of thrombus, calcification, bifurcation or ostial location, or chronic occlusion) and 1,790 patients with only simple lesions treated. Complex lesion interventions were associated (p <0.05) with more sustained major dissections, distal embolization, side branch occlusion, and persistent flow reduction. Patients with treated complex lesions had a lower procedural success rate (93.8% vs 97.3%, p <0.001) and increased in-hospital rates (p <0.001) of death (2.0% vs 0.6%), death/myocardial infarction [MI] (5.2% vs 2.4%), or death/MI/coronary artery bypass graft [CABG] surgery (6.5% vs 2.9%). After adjustment for potential confounders, patients treated for multiple complex lesions were more likely to experience the in-hospital combined end points of death/MI (odds ratio 3.22, 95% confidence interval 2.10 to 4.92), or death/MI/CABG (odds ratio 2.55, 95% confidence interval 1.71 to 3.80). At 1 year, patients with treated complex lesions were more likely (p <0.001) to die (6.2% vs 3.7%), suffer death/MI (11.7% vs 7.5%), or death/MI/CABG/repeat PCI (27.2% vs 23.4%). Patients treated for multiple complex lesions were approximately 50% more likely to die or to have major adverse events than with patients only treated for simple lesions. An increased in-hospital adverse clinical event rate was independently noted for thrombotic, bifurcation, and calcified lesions, and bifurcation lesions had worse long-term event rates.