Approximately 70-80% of newborns less than 28 weeks' gestational age require pharmacologic and/or surgical intervention to close a hemodynamically significant patent ductus arteriosus (PDA). Indomethacin has been the pharmacologic treatment of choice and has also been used prophylactically in very premature neonates to prevent PDA. The drug, however, is associated with renal and gastrointestinal adverse effects. In July 2006, intravenous ibuprofen lysine became available in the United States for treatment of hemodynamically significant PDA. The mechanism of action for both indomethacin and ibuprofen lysine is through inhibition of prostaglandin synthesis, resulting in ductal constriction. Both drugs appear to be equally efficacious in closing echocardiographically confirmed PDA. Ibuprofen lysine has demonstrated significantly less effects on cerebral, renal, and mesenteric blood flow in premature neonates when compared with indomethacin. A transient but significant increase in serum creatinine concentration, decrease in urine output, and increase in frequency of oliguria were observed with indomethacin when compared with ibuprofen lysine. However, the rate of reopening of the ductus after pharmacologic closure and the need for rescue therapy were not different between the two drugs. In addition, no differences were noted in other outcomes such as frequency of intraventricular hemorrhage, necrotizing enterocolitis, or chronic lung disease, as well as in duration of mechanical ventilation and length of hospital stay. When administered prophylactically, ibuprofen lysine did not prevent intraventricular hemorrhage nor provide any neurodevelopmental benefits. In addition, ibuprofen lysine has not been adequately studied in neonates of 27 weeks' gestational age or younger. Ibuprofen lysine is as efficacious as indomethacin in treating hemodynamically significant PDA in neonates greater than 27 weeks' gestational age.