BACKGROUND: Randomized controlled trials have demonstrated the efficacy of selected beta-blockers for preventing cardiovascular (CV) events in patients following myocardial infarction (MI) or with heart failure (HF). However, the effectiveness of beta-blockers for preventing CV events in patients with hypertension has been questioned recently, but it is unclear whether this is a class effect. METHODS: Using electronic medical record and health plan data from the Cardiovascular Research Network Hypertension Registry, we compared incident MI, HF, and stroke in patients who were new beta-blocker users between 2000 and 2009. Patients had no history of CV disease and had not previously filled a prescription for a beta-blocker. Cox proportional hazards regression was used to examine the associations of atenolol and metoprolol tartrate with incident CV events using both standard covariate adjustment (n = 120,978) and propensity score-matching methods (n = 22,352). RESULTS: During follow-up (median, 5.2 years), there were 3517 incident MI, 3272 incident HF, and 3664 incident stroke events. Hazard ratios for MI, HF, and stroke in metoprolol tartrate users were 0.99 (95% CI, 0.97-1.02), 0.99 (95% CI, 0.96-1.01), and 0.99 (95% CI, 0.97-1.02), respectively. An alternative approach using propensity score matching yielded similar results in 11,176 new metoprolol tartrate users, who were similar to 11,176 new atenolol users with regard to demographic and clinical characteristics. CONCLUSIONS: There were no statistically significant differences in incident CV events between atenolol and metoprolol tartrate users with hypertension. Large registries similar to the one used in this analysis may be useful for addressing comparative effectiveness questions that are unlikely to be resolved by randomized trials.