Studies in premature animals suggest that 1) prolonged tight, constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [NG- monomethyl- L- argini- ne (L- NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L- NMMA in newborns born at < 28 weeks’ gestation who had persistent ductus flow by Doppler after an initial three- dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h) . Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h)- plus a 72- hour L- NMMA infusion]. Thirty- eight newborns received three additional indomethacin doses (without LNMMA) and served as a comparison group. Ninety- two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L- NMMA infusions were limited in dose and duration by acute side effects. Doses of 10- 20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L- NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at < 28 weeks’ gestation. However, the combined administration of L- NMMA and indomethacin was limited by acute side effects in this treatment protocol. Studies in premature animals suggest that 1) prolonged tight, constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [NG-monomethyl-L-argini- ne (L- NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Thus, we conducted a phase I and II study of combined treatment with indomethacin and L- NMMA in newborns born at <28 weeks’ gestation who had persistent ductus flow by Doppler after an initial three-dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg / kg / 24 h). Twelve infants were treated with the combined treatment protocol [ Additional indomethacin doses (0.1 mg / kg / 24 h) - plus a 72-hour L-NMMA infusion]. Thirty- eight newborns received three additional indomethacin doses (without LNMMA) and served as a comparison group. Ninety- two per cent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L- NMMA infusions were limited in Doses of 10- 20 mg / kg / h increased serum creatinine and systemic blood pressure. At 5 mg / kg / h, serum creatinine was stable but systemic blood still limited L-NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at <28 weeks’ gestation. However, the combined administration of L- NMMA and indomethacin was limited by acute side effects in this treatment protocol.