Management of patent ductus arteriosus (PDA) in preterm infants is one of the most controversial topics in neonatal medicine. The availability of different pharmacotherapeutic options often poses a practical challenge to the practising neonatologist as to which one to choose as a therapeutic option. Our objectives are to determine the relative merits of the available pharmacotherapeutic options for the management of PDA.We will conduct a systematic review of all randomised controlled trials evaluating the use of intravenous or oral: indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. The primary outcome is failure of closure of the PDA. Secondary outcomes are neonatal mortality, need for surgical closure, duration of ventilator support, chronic lung disease, intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleeding, time to full enteral feeds and oliguria. We will search Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach). Subgroup analysis according to gestational age, birth weight, different doses of interventions, time of administration of the first dose of the intervention, and echocardiographic definition of haemodynamically significant PDA and ROB are planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data are available.The results will help to reduce the uncertainty about the safety and effectiveness of the interventions, will identify knowledge gaps or will encourage further research for other therapeutic options. Therefore, its results will be disseminated through peer-reviewed publications and conference presentations. On the basis of the nature of its design, no ethics approval is necessary for this study.CRD42015015797.