Atrial fibrillation (AF) is the most common complication of coronary artery bypass grafting (CABG), usually occurring on the second or third post-operative day. Post-operative AF is associated with prolonged hospital stay and increased costs. In several randomized trials, prophylactic oral beta-blocker reduced the incidence of post-operative AF. Theoretically, intravenous beta-blocker regimen with its rapid onset of action and ease of dose titration should be more efficacious than oral beta-blocker. We conducted an open-label randomized controlled pilot study, compared the efficacy of intravenous esmolol and an oral beta-blocker regimen for prevention of post-operative AF. Fifty patients at high-risk of developing post-operative AF (P wave duration >140 ms on signal averaged (SA) ECG) were randomized to either 24-hours of intravenous esmolol treatment post-CABG followed by oral beta-blocker or standard oral beta-blocker treatment. Seven (26%) out of 27 patients in the esmolol group and 6 (26%) out of 23 patients in the oral beta-blocker group developed post-operative AF (p = NS). The day of onset and duration of AF was similar between the two groups. In the esmolol group, 11 (41%) patients developed adverse effects, mostly hypotension, compared to only one patient (4%) in the oral beta-blocker group (p = 0.006). The result of this pilot study showed that intravenous esmolol compared to oral beta-blocker offers no advantage in preventing post-operative AF and is associated with increased adverse events. Thus, all patients without contraindication should receive oral beta-blocker before and after cardiac surgery to prevent post-operative AF.