Patients with hypertension who develop atrial premature complexes (APCs) are at a particularly high risk for atrial fibrillation (AF). We sought to identify medications and modifiable risk factors that could reduce the risk of AF imposed by presence of APCs in such a high risk group. This analysis included 4,331 participants with treated hypertension from the Reasons for Geographic and Racial Differences in Stroke study who were free of AF and cardiovascular disease at the time of enrollment (2003-2007). APCs were detected in 8.2% (n = 356) of the participants at baseline. During a median follow-up of 9.4 years, 9.9% (n = 429) of the participants developed AF. Participants with APCs, compared with those without, were more than twice as likely to develop AF (Odds ratio [95% confidence interval]: 2.36[1.75, 3.19]). This association was significantly weaker in statin users than nonusers (Odds ratio [95% confidence interval]:1.42[0.81,2.48] vs 3.01[2.11,4.32], respectively; interaction p-value = 0.02), and in angiotensin-II receptor blocker users than nonusers (Odds ratio [95% confidence interval]:1.31[0.66,2.61] vs 2.78[1.99,3.89], respectively; interaction p-value = 0.05). Borderline weaker associations between APCs and AF were also observed in alpha-blocker users than nonusers, nondiabetics than diabetics, and in those with systolic blood pressure level 130 to 139 mm Hg compared with those with other systolic blood pressure levels. No significant effect modifications were observed by use of other medications or by presence of other cardiovascular risk factors. In conclusion, the significant AF risk associated with APCs in patients with hypertension could potentially be reduced by treatment with angiotensin-II receptor blockers and statins along with lowering blood pressure and management of diabetes.