Different antihypertensive drug classes may alter risk for atrial fibrillation. Some studies suggest that drugs that interfere with the renin-angiotensin system may be favorable because of their effect on atrial remodeling. To assess and compare the relative risk for incident atrial fibrillation among hypertensive patients who receive antihypertensive drugs from different classes. Nested case-control analysis. The United Kingdom-based General Practice Research Database, a well-validated primary care database comprising approximately 5 million patient records. 4661 patients with atrial fibrillation and 18,642 matched control participants from a population of 682,993 patients treated for hypertension. A comparison of the risk for atrial fibrillation among hypertensive users of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), or beta-blockers with the reference group of users of calcium-channel blockers. Patients with clinical risk factors for atrial fibrillation were excluded. Current exclusive long-term therapy with ACE inhibitors (odds ratio [OR], 0.75 [95% CI, 0.65 to 0.87]), ARBs (OR, 0.71 [CI, 0.57 to 0.89]), or beta-blockers (OR, 0.78 [CI, 0.67 to 0.92]) was associated with a lower risk for atrial fibrillation than current exclusive therapy with calcium-channel blockers. Blood pressure changes during treatment courses could not be evaluated, and risk for bias by indication cannot be fully excluded in an observational study. In hypertensive patients, long-term receipt of ACE inhibitors, ARBs, or beta-blockers reduces the risk for atrial fibrillation compared with receipt of calcium-channel blockers. None.