Atrial fibrillation (AF) is prevalent in the elderly, in patients with hypertension, and in patients with coronary artery disease (CAD). We hypothesized that statin therapy might be effective in preventing AF in patients with CAD and examined this hypothesis in a sample of patients with chronic stable CAD without AF, followed prospectively at a large outpatient cardiology practice. The association between statin use and the risk of developing AF was examined univariately and then with adjustment for potential confounding factors. Four hundred forty-nine men and women between the ages of 40 and 87 years were followed for an average of 5 years. Fifty-two patients (12%) developed AF during follow-up. Statin therapy was used by 59% of the patients during the study period and was associated with a significantly reduced risk of developing AF (crude odds ratio, 0.48, 95% confidence interval 0.28 to 0.83). This association remained significant after adjustment for potential confounders, including age, hypertension, left ventricular systolic function, occurrence of heart failure or acute ischemic events, and baseline cholesterol and changes in cholesterol levels (adjusted odds ratio 0.37, 95% confidence interval 0.18 to 0.76). Use of statins in patients with chronic stable CAD appears to be protective against AF. The underlying mechanism for this effect is unknown but appears to be independent of the reduction in serum cholesterol levels.