In spite of the progress made in acute angiographic evaluation and obtaining durable reperfusion of acute myocardial infarction (AMI) in the past two decades, cardiac free wall rupture (FWR) is still one of the causes of mortality following AMI. In this study, we evaluated the role of thrombolysis in the risk of FWR in AMI patients treated with acute percutaneous coronary intervention (PCI). Among 3,786 consecutive AMI patients seen between 1985 and 2003, 3,066 patients were treated by primary PCI or rescue PCI, with or without additional thrombolysis. FWR occurred in 24 of 3,066 patients (0.8%) treated by PCI; female gender (1.4% vs 0.6%, P=0.001), age >75 years, (1.4% vs 0.6%, P=0.001) left main coronary artery (LMCA)-related infarction, (4.5% vs all other arteries, P=0.015), and thrombolytic use (3.1% vs 0.4%, P<0.001) were all associated with higher rates of FWR by univariate analysis. In patients treated with PCI and thrombolysis, FWR occurred in 2.7% with optimal PCI results but in only 4.9% if PCI was unsuccessful (P=NS). The incidence of FWR in patients with optimal PCI without thrombolysis was 0.4% (P<0.001). Multivariable analysis identified thrombolytic use (odds ratio [OR]: 8.49, 95% confidence interval [CI]: 3.66-19.7, P<0.001), LMCA-related infarction (OR: 7.06, 95% CI: 1.89-26.4, P=0.004), and female gender (OR: 3.02, 95% CI: 1.27-7.21, P=0.013) as independent predictors of FWR. Thrombolysis is one of the contributing causes of FWR in AMI patients undergoing PCI, even when PCI is successful.