Peripheral intravenous cannula (PIVC) insertion is one of the most common invasive procedures performed in neonates and is frequently associated with adverse events. There are no studies in the neonatal population looking at the possibility of reducing the risk of PIVC-related complications by elective replacement of PIVC. A randomised, non-blinded, control trial was conducted in a tertiary level neonatal unit in Melbourne, Australia, to examine rates of extravasation in neonates with elective replacement of PIVC as compared to standard practice. Neonates born at 32 weeks of gestation or more were randomly assigned to have their PIVC replaced electively (every 72–96 h) or when clinically indicated in a 1:1 allocation ratio after parental consent. Primary outcome studied was rate of extravasation. Secondary outcomes included rates of phlebitis, leakage or spontaneous dislodgement of PIVC. One hundred thirteen infants were enrolled. Extravasation was noted in 33 (60%) of standard practice group vs. 28 (48.3%) of elective replacement (RR 0.80, CI 0.57–1.13, p = 0.21) infants. Time to first extravasation was similar between the groups (hazard ratio 0.69, CI 0.42–1.15). Extravasation events per 1000 IV hours were also similar between groups. Similar results were seen by both intention to treat and per protocol analyses. There was an increase in leaking rates (HR1.98, CI 1.03–3.81, p = 0.04) in the elective group, while phlebitis and spontaneous dislodgement rates were similar to standard group. Conclusion: Elective replacement of PIVC in neonates is not associated with reduction in extravasation rates. Trial registration: This trial has been registered with the Australian and New Zealand Clinical Trials Register. Identifier: ACTRN12615000827538.What is Known:• The reported incidence of extravasation injury is as high as 70% in the neonatal and paediatric population and has an association with cannula dwell time.• Adult studies have done to look at the possibility of reducing intravenous cannula-related complications with routine replacement of the cannulas but no similar studies have been done in the neonatal population.What is New:• Routine replacement of intravenous cannula in neonates between 72 and 96 h of use does not reduce the rate of extravasation injuries.• There might be some added complications associated with such a practice.