Moderate to severe portopulmonary hypertension (PPHTN) increases the risks of orthotopic liver transplantation (OLT). Epoprostenol is an effective treatment of PPHTN, but long-term effects on pulmonary hemodynamics or liver function in PPHTN are poorly defined. We sought to describe the long-term effects of treatment with or without epoprostenol on pulmonary hemodynamics, liver biochemistries, and survival in patients with moderate to severe PPHTN at a single center. A large retrospective cohort was identified with moderate to severe PPHTN diagnosed before OLT. Baseline and follow-up pulmonary hemodynamics and liver biochemistries were compared and outcomes assessed. Nineteen patients were treated with epoprostenol and 17 were not treated with epoprostenol. There were significant improvements in mean pulmonary artery pressure (MPAP, 48.4-36.1 mm Hg; P < 0.0001), pulmonary vascular resistance (PVR, 632-282 dynes · s · cm−5; P < 0.0001), and cardiac output (5.7 to 7.7 L/min; P = 0.0009) with epoprostenol after a median of 15.4 months. Liver biochemistries did not change significantly, and survival did not seem to differ between the 2 groups (hazard ratio, 0.85; P = 0.77). In the epoprostenol group, patients who survived had greater absolute changes in MPAP, transpulmonary gradient, and PVR than those who died. Two patients in the epoprostenol group successfully underwent OLT. Long-term epoprostenol therapy greatly improves pulmonary hemodynamics in patients with PPHTN. Liver biochemistries are not greatly changed. Survival seemed not to differ between treatment groups. A minority of patients treated with epoprostenol will improve sufficiently to undergo OLT. Liver Transpl 13:875–885, 2007. © 2007 AASLD.