Ibuprofen has been proposed as a preferential alternative to indomethacin in treating patent ductus arteriosus (PDA), because it is purported to have less renal, mesenteric, and cerebral vasoconstrictive effects. However, short and long-term safety concerns regarding ibuprofen remain. Continuous slow infusion of indomethacin also eliminates peripheral vasoconstriction and may thus offer similar benefits to ibuprofen without safety concerns. In this study, our objective was to show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function, and blood flow velocities in the renal, superior mesenteric, and anterior cerebral arteries. Sixty four prematures with PDA were randomly, prospectively assigned to either treatment. PDA closure rates were similar (74 versus 59%; p = 0.123). Nine indomethacin-treated babies (29%) versus twelve ibuprofen babies (38%) underwent repeated therapy (p = 0.656). Two indomethacin and four ibuprofen infants required surgical ligation (p = 0.672). Serum creatinine, oliguria, estimated glomerular filtration rate, and fractional excretion of sodium were similar in both groups, as were blood flow velocity parameters in the vessels studied. There were no differences in necrotizing enterocolitis, BPD, intraventricular hemorrhage, and/or retinopathy of prematurity. In conclusion, PDA treatment with either continuous indomethacin infusion or ibuprofen was equally devoid of adverse renal effects and/or peripheral vasoconstrictive effects.