AIMS: Major bleeding after percutaneous coronary intervention (PCI) is an independent risk factor for early and late mortality. We developed and validated a risk score predictive of major bleeding after PCI using the femoral approach. METHODS AND RESULTS: Baseline clinical and procedural variables from two contemporary, multicentre, randomized PCI trials were used for risk score development (the REPLACE-2 trial, n = 6002) and validation (the REPLACE-1 trial, n = 1056). On the basis of the odds ratio, independent risk factors were assigned a weighted integer, the sum of which comprised a total risk score. Seven variables were identified as independent correlates of major bleeding (age >55 years, female gender, estimated glomerular filtration rate <60 mL/min/1.73 m(2), pre-existing anaemia, administration of low-molecular-weight heparin within 48 h pre-PCI, use of glycoprotein IIb/IIIa inhibitors, and intraaortic balloon pump use). In the development set, the risk of major bleeding varied from 1.0% in patients without risk factors to 5.4% in high-risk patients. The discriminatory power of this risk model was confirmed in the validation data set (area under the receiver operating curve = 0.62). CONCLUSION: A simple risk score of baseline clinical and procedural variables is useful to predict the incidence of major peri-procedural bleeding after contemporary PCI using the femoral approach.