In preterm neonates, patent ductus arteriosus (PDA) is associated with impaired lung function, and reduced renal, gastrointestinal and cerebral perfusion,1, 2, 3, 4, 5, 6, 7, 8, 9 as well as higher rates of mortality and major morbidities such as intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and acute kidney injury (AKI).10, 11, 12, 13, 14 Management of PDA, the most common cardiovascular disorder of prematurity, is a key component of neonatal intensive care practice.15, 16, 17 Despite decades of research and investigation of several pharmacological agents, the failure rate for monotherapy with cyclooxygenase inhibitors (COXi) or acetaminophen for the first treatment course remains unacceptably high, especially in extremely low gestational age neonates (ELGANs, GA at birth <28 weeks).18, 19, 20, 21, 22 Combination therapy, comprising acetaminophen and ibuprofen, is a novel strategy that may facilitate PDA closure via additive or synergistic action on two separate pathways inhibiting prostaglandin production. In this review, we examine the potential clinical impact of treatment failure in ELGANs with significant PDA, highlight the biological rationale in support of studying a combination treatment regimen and review the efficacy and effectiveness of combination therapy reported in randomized and observational studies.