Excess nitric oxide is a mediator of the hypotension in septic shock. Nitric oxide dilates vascular smooth muscle through activation of soluble guanylate cyclase. We report the increase in blood pressure caused by methylene blue (MB), a soluble guanylate cyclase inhibitor, in five neonates with presumed septic shock unresponsive to colloids, inotropic agents, and corticosteroids. MB was given intravenously at a dose of 1 mg/kg during a 1-hour period. MB increased blood pressure in each patient (average, 33% +/- 20%). Blood pressure subsequently decreased to near baseline values in three patients, who then received a second infusion of MB. Blood pressure again increased in these patients. Three of five patients were weaned from inotropic support within 72 hours. Three of five patients survived and were discharged home. We suggest that MB increased blood pressure in these neonates with refractory hypotension.