Eplerenone is reported to reduce the development of atrial fibrillation (AF). The aim of this study was to clarify the mechanism of eplerenone for AF prevention from the viewpoint of P wave morphology, which is reported to correlate with atrial fibrosis. Thirty-five patients with hypertension, who were randomized to receive eplerenone (n=16) or amlodipine (n=19) for 1 year, were evaluated. P wave signal-averaged electrocardiography was recorded at baseline and 1 year after entry, and P wave duration (Ad) and P wave dispersion (P-disp) were obtained. Serum levels of intact procollagen type I N-terminal propeptide (PINP) and N-terminal procollagen-III peptide (PIIIP) were also measured. There were no significant differences in baseline clinical characteristics including Ad, P-disp, and the decrease in blood pressure at 1-year follow-up between the two groups. Ad and P-disp (mean±standard deviation) significantly increased in patients on amlodipine after 1 year (140±21 ms to 139±19ms vs 132±10 ms to 136±12ms, P<0.01 and 14±7 ms to 9±4ms vs 12±5 to 16±8, P<0.01, respectively). PINP was significantly more decreased in patients with eplerenone than amlodipine (56.6±30.4 μg/mL to 46.6±19.4 μg/mL vs 41.5±16.2 μg/L to 48.7±21.3 μg/L, P<0.01). Percent changes of Ad, P-disp, PINP, and PIIIP were significantly smaller in patients with eplerenone than amlodipine (0.0±4.7% vs 3.2±4.4%, P<0.05,-28.6±31.0% vs 46.3±73.0%, P<0.01,-5.6±38.1% vs 22.7±42.7%, P<0.05, and-9.2±25.1%vs 7.4±19.0%, P<0.05, respectively). Eplerenone reduced the increase of Ad and P-disp with a decrease of PINP and PIIIP, which might translate into reduction of atrial fibrosis. This study showed that eplerenone may be useful as upstream therapy for AF in patients with hypertension.