AIMS: The CHA2DS2VASc score is used to evaluate the risk of thromboembolic events in patients with non-valvular atrial fibrillation. We assessed the prognostic yield of CHA2DS2VASc for new-onset atrial fibrillation, cardiovascular morbidity and mortality in a non-atrial fibrillation population. METHODS: We analysed a population-based cohort of 22,179 middle-aged individuals with (n = 3542) and without (n = 18,367) a history of atrial fibrillation; we grouped the population into five CHA2DS2VASc strata (0-1-2-3-≥4), and compared the risk of major adverse cerebro-cardiovascular events and mortality. Furthermore, we analysed the annual incidence of atrial fibrillation across different CHA2DS2VASc strata. RESULTS: Over a median follow-up of 15 years, 1572 patients (6.9%) had ischaemic strokes, 2162 (9.5%) coronary events and 5899 (26%) died. The cumulative incidence of ischaemic stroke in CHA2DS2VASc ≥ 4 subjects without atrial fibrillation was similar to patients with atrial fibrillation and CHA2DS2VASc 2, with a 10-year crude incidence rate of 0.91 (95% confidence interval (CI) 0.68-1.19) and 1.13 (95% CI 0.93-1.36) ischaemic strokes per 100 patient-years, respectively. CHA2DS2VASc in a non-atrial fibrillation population showed higher predictive accuracy for ischaemic stroke compared with an atrial fibrillation population (area under the curve 0.60 vs. 0.56; P = 0.001). In multivariable Cox regression analysis, CHA2DS2VASc ≥ 2 was an independent predictor of all-cause death (adjusted hazard ratio (aHR) 2.58; 95% CI 2.42-2.76), cardiovascular death (aHR 3.40; 95% CI 2.98-3.89), ischaemic stroke (aHR 2.20; 95% CI 1.92-2.53) and coronary events (aHR 1.83; 95% CI 1.63-2.04). The cumulative incidence of atrial fibrillation was greater with increasing CHA2DS2VASc strata, with an absolute annual incidence of more than 2% per year if CHA2DS2VASc ≥ 4. CONCLUSION: The CHA2DS2VASc score is a sensitive tool for predicting new-onset atrial fibrillation and adverse outcomes in subjects both with and without atrial fibrillation.