Hepatopulmonary syndrome (HPS) is characterized by pulmonary vasodilation and subsequent hypoxemia in the setting of hepatic dysfunction. There is currently no pharmacologic intervention that has been shown to significantly affect outcomes and liver transplantation remains the mainstay of therapy. Unfortunately, patients undergoing liver transplantation are at high risk of significant hypoxemia and mortality in the early postoperative period. In the following case series, we present two cases of patients with severe HPS who underwent liver transplantation and experienced marked hypoxemia in the early postoperative period. In both cases, we successfully treated the patients with inhaled nitric oxide for their severe refractory life-threatening hypoxemia which led to immediate and dramatic improvements in their oxygenation. Although the use of inhaled nitric oxide in patients with HPS has been sporadically reported in pediatric literature and in animal studies, to our knowledge, our cases are the first recorded in adult patients.