Aim: To assess the performance of the QRISK score for predicting cardiovascular disease (CVD) in an independent UK sample from general practice and compare with the Framingham score. Design: Prospective open cohort study Setting: UK general practices contributing to the THIN and QRESEARCH databases. Cohort: The THIN validation cohort consisted of 1.07 million patients, aged 35–74 years registered at 288 THIN practices between 1 January 1995 and 1 April 2006. The QRESEARCH validation cohort consisted of 0.61 million patients from 160 practices (one-third of the full database) with data until 1 January 2007. Patients receiving statins, those with diabetes or CVD at baseline were excluded. End point: First diagnosis of CVD (myocardial infarction, coronary heart disease (CHD), stroke and transient ischaemic attack) recorded on the clinical computer system during the study period. Exposures: Age, sex, smoking status, systolic blood pressure, total/high-density lipoprotein cholesterol ratio, body mass index, family history of premature CHD, deprivation and antihypertensive medication. Results: Characteristics of both cohorts were similar, except that THIN patients were from slightly more affluent areas and had lower recording of family history of CHD. QRISK performed better than Framingham for every discrimination and calibration statistic in both cohorts. Framingham overpredicted risk by 23% in the THIN cohort, while QRISK underpredicted risk by 12%. Conclusion: This analysis demonstrated that QRISK is better calibrated to the UK population than Framingham and has better discrimination. The results suggest that QRISK is likely to provide more appropriate risk estimates than Framingham to help identify patients at high risk of CVD in the UK.