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Heart failure (HF) is associated with a prothrombotic state, resulting in an increased risk for thrombo-embolic events. Studies suggest a reduced prothrombotic state when non-selective beta-blockers relative to selective beta-blockers are given. We studied the influence of non-selective beta-blockers compared with selective beta-blockers on the occurrence of arterial and venous thrombo-embolic events in patients with HF.Data were obtained from the PHARMO Record Linkage System, a population-based registry of pharmacy records linked with hospital discharge records in The Netherlands. In the period of 1998–2007, 20 870 patients were hospitalized for HF. We used Cox regression analysis with time-varying beta-blocker covariate to assess the difference in the incidence of thrombo-embolic events [acute coronary syndrome (ACS), stroke, or pulmonary embolism] among patients. Median follow-up was 2.0 years (inter-quartile range: 0.7–4.1). Directly after discharge, 6558 patients were prescribed a selective beta-blocker and 2202 patients a non-selective beta-blocker. The hazard ratio (HR) for any thrombo-embolic event for non-selective beta-blockers compared with selective beta-blockers was 0.76 [95% confidence interval (CI): 0.64–0.89]. After adjustment, the difference remained (HR 0.84, 95% CI: 0.72–0.99). The effect was most prominent for ACS (HR 0.78, 95% CI: 0.65–0.93), and not clear for stroke (HR 1.00, 95% CI: 0.67–1.50) or pulmonary embolism (HR 1.33, 95% CI: 0.66–2.71).In patients with HF, the use of non-selective beta-blockers was associated with a lower risk of thrombo-embolic events than selective beta-blockers. Whether this beneficial effect is caused by the additional beta2-receptor blockade remains to be elucidated. These findings need to be validated in a well-designed randomized study.