Hypoxic pulmonary vasoconstriction (HPV) is inhibited by inhaled nitric oxide (NO) in healthy animals and is blunted in endotoxemia. We investigated whether the loss of HPV during sepsis could be reversed by NO synthase (NOS) inhibition. Hypoxic challenges were induced in intubated, awake sheep breathing 100% nitrogen to the left lung and 100% oxygen to the right lung. HPV was assessed as the decrease in left pulmonary blood flow during hypoxia, measured with an ultrasonic flow probe around the left pulmonary artery. Group I (n = 5) received carrier solutions and Groups II (n = 6) and III (n = 8) received an infusion containing Pseudomonas aeruginosa. After 24 h, Group III also received an infusion of 6.6 mg · kg · h^{− 1} N^ω-monomethyl-L-arginine (L-NMMA). After 24 h of sepsis, HPV decreased from 60 ± 9% in Group II and 56 ± 4% in Group III to 27 ± 2% and 26 ± 4%, respectively. Group I showed no change in HPV. During infusion of L-NMMA, HPV increased to 38 ± 4%. Pulmonary shunt during hypoxia increased in Group III to 161 ± 10% of its baseline value, and decreased to 121 ± 11% during infusion of L-NMMA. We conclude that L-NMMA improves but does not restore HPV, indicating that other vasodilatatory mediators besides NO also influence HPV in sepsis.