Introduction There is currently no effective treatment for patients with HFpEF and pulmonary hypertension (PH-HFpEF). We hypothesized that levosimendan (LEVO), a calcium sensitizer with inotropic and vascular smooth muscle relaxant properties, would improve hemodynamics and exercise capacity in PH-HFpEF. Methods We conducted a multicenter, double-blind, placebo-controlled trial testing the effects of once-weekly IV LEVO on hemodynamics and 6 minute walk distance (6MWD) in patients with PH-HFpEF. Participants with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II-III symptoms underwent 6MW and invasive hemodynamic assessments at rest, passive leg raise (PLR) and supine cycle exercise (EX) at baseline and following a 24-hour infusion of LEVO (0.1 μg/kg/min). Hemodynamic responders, defined as those with ≥4 mmHg reduction of EX PCWP, were then randomized, double blind, to a once weekly infusion of LEVO (up to 0.1 μg/kg/min) or placebo for 6 weeks, at which point hemodynamic assessments and 6MW test were repeated. The primary endpoint was between-group difference in the change of EX PCWP. Results Of 44 subjects enrolled, 37 (84%) qualified as responders and were randomized to LEVO (n=18) or placebo (n=19). Patients (69±9 years old, 61% women) displayed severe combined pre- and post-capillary PH at baseline (resting mPAP 41±10, PCWP 25±6 mmHg pulmonary vascular resistance 3.4±2.7). At 6-weeks, LEVO had no significant effect on EX PCWP compared to placebo (-1.4 mmHg, 95% CI, -7.7 to 4.8, p=0.65). However, in a mixed-effect repeated measure regression analysis incorporating rest, PLR, and EX stages, LEVO reduced PCWP by 3.9±2.0 mmHg as compared to placebo (p=0.047, Figure). As compared to placebo, LEVO improved 6MWD by 29 m (95% CI, 3 to 56, p=0.033). LEVO was well-tolerated with no difference in the incidence of adverse events compared to placebo. Conclusions In patients with PH-HFpEF, once-weekly treatment with LEVO for 6 weeks reduced PCWP and increased 6MWD without adverse effects. A phase 3 study to definitively test the safety and efficacy of LEVO as a treatment for PH-HFpEF is warranted.