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Introduction: Higher progesterone concentrations are protective against drug‐induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug‐induced torsades de pointes (TdP). Methods and Results: Female New Zealand white rabbits (2.5‐3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21‐day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs‐Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15‐minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo‐treated rabbits (3.8 [range, 2.8‐5.1] vs 0.7 [0.4‐1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22‐72] vs 53 [34‐62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone‐treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone‐treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short‐term beat‐to‐beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone‐treated rabbits. Conclusions: Pretreatment with progesterone reduces the incidence of drug‐induced TdP, bigeminy, and trigeminy in isolated perfused AV node‐ablated rabbit hearts. [ABSTRACT FROM AUTHOR]