Current evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce the incidence of new atrial fibrillation (AF) in a variety of clinical conditions, including the treatment of left ventricular dysfunction or hypertension. Here we assessed whether ACEIs and ARBs could decrease incidence of new-onset AF in patients with end-stage renal disease (ESRD). We identified patients from the Registry for Catastrophic Illness, a nation-wide database encompassing almost all of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios for new-onset AF. Among 113,186 patients, 13% received ACEIs, 14% received ARBs therapy, and 9% received ACEIs or ARBs alternatively. After a median follow-up of 1524 days, the incidence of new-onset AF significantly decreased in patients treated with ACEIs (hazard ratio 0.587, 95% confidence interval 0.519-0.663), ARBs (0.542, 0.461-0.637), or ACEIs/ARBs (0.793, 0.657-0.958). The prevention of new-onset AF was significantly better in patients taking longer duration of ACEI or ARB therapy. The effect remained robust in subgroup analyses. Thus both ACEIs and ARBs appear to be effective in the primary prevention of AF in patients with ESRD. Hence, renin-angiotensin system inhibition may be an emerging treatment target for the primary prevention of AF.