We previously have shown that pulmonary hypertension (PH)-induced right ventricular failure (RVF) is associated with increased incidence of sudden death caused by spontaneous ventricular fibrillation (VF). We also discovered that estrogen (E2) therapy rescues severe PH and RVF and results in 100% survival. Here we hypothesized that E2 abolishes spontaneous VF associated with RVF by restoring RVEF, reversing fibrosis and restoring PH-induced downregulation of repolarizing K-channel proteins Kv1.5 and KCNE-2 and SERCA-2a expression. Chronic PH-associated RVF was induced in male rats by s.c. monocrotaline (MCT, 60 mg/kg, n=10). Some MCT-rats were treated with E2 (42.5 ug/kg/day, s.c.) from day 21 (severe PH-stage) to day-30 (n=8). Saline treated rats served as control (n=8). At ∼day 30, hearts were studied in isolated-perfused Langendorff setting. RV-epicardial activation pattern was optically mapped using fluorescent voltage-sensitive dye (RH-237). By ∼day 30, 30% RVF rats died suddenly but none in the control or E2-groups. RVF hearts manifested EADs and spontaneous VF during normal Tyrode’s perfusion with wavefront dynamics supported by both focal and multiple wavelet patterns. No VF was initiated in any of the control or E2-treated hearts. SERCA-2a was reduced (∼15-fold) in RVF (0.06±0.01 vs. 1±0.26 control) that was reversed in E2-group (0.77±0.13, p<0.05 vs. RVF). Kv1.5 was reduced ∼8 fold in RVF (0.12±0.03 vs. 1±0.18 in control, p<0.05) and E2 partially restored Kv1.5 (0.46±0.06, p<0.05). KCNE2, an ancillary K-channel subunit, was reduced ∼3-fold in RVF (0.3±0.1 vs. 1±0.1, p<0.05) that was reversed by E2 (0.9±0.05, p<0.05). RVF was associated with moderate RV-fibrosis and severe reduction in RV-ejection fraction (RVEF) from 65±1 to 33±3%. E2- group did not show any fibrosis and RVEF was preserved (60±2%). In conclusion, E2-therapy rescues RVF and prevents VF by reversing PH-induced RV-fibrosis and reduced repolarization-reserve.