Although inhaled nitric oxide (INO) and high frequency oscillatory ventilation (HFOV) are effective therapies in severe persistent pulmonary hypertension of the newborn (PPHN), the efficacy of these therapies in neonates with sepsis and PPHN are unknown. To determine the response rate to INO and HFOV and to identify factors associated with poor responses in septic newborns we analyzed the data from a multicenter trial of INO and HFOV in neonates with PPHN. Criteria for enrollment included: gestational age ≥ 34 weeks, Pa02 <80 torr despite ventilation with Fi02 = 1.00, and echocardiographic signs of severe PPHN. Infants were randomized to INO with conventional ventilation or HFOV. Failure to sustain Pa02 > 60 torr led to treatment with the alternative or combined therapy (INO+HFOV). Of 205 neonates enrolled in this study, 22 were identified as septic by blood culture (20 with group B strep). Eleven infants improved and survived without ECMO(Responders). Of the eleven responders, 4 responded to INO, 3 responded to HFOV, 4 required INO and HFOV. Eleven infants did not respond and were treated with ECMO (N=8 with 5 deaths)or died without ECMO (N=3). There were no differences in AaD02 and blood pressure between responders and non-responders at study entry. However, non-responders had lower pH (7.43±.08 vs. 7.13±.19,P<.001), lower base deficits (-2±4 vs.-15±6P<.001), and higher PC02 (32±5 44±14 P<.05). All infants with pH>7.31 at study entry responded and 100% survived without ECMO. We conclude that: 1. septic newborns with severe PPHN have a 50% response rate to treatment strategies which include INO and HFOV; 2. non-response to these therapies is associated with high mortality (73%) despite ECMO therapy; and 3. metabolic acidosis is a marker of poor responsiveness.