Background: Remifentanyl (R) is a synthetic mu-opioid agonist whose unique metabolism by blood and tissue esterases yields a rapid-onset, ultrashort elimination half-life and short recovery time. Remifentanyl is particularly suitable for invasive procedures, because it is easier to handle than Fentanyl.Aims: The aim of this study was to define the safety and efficacy of R during percutaneous venous line inserction (PICC) in preterm infants. Patients and methods: Thirty-five preterm (mean gestational age 29 + 3 SD, r. 23–36 wks), who underwent elective positioning of a PICC line at a mean postnatal age of 8 + 4 SD days, were randomly assigned to receive R or non-pharmacological measures (C). R infusion was started at a rate of 0.006 mcg/kg/min and then titrated every 10 minutes according to the level of analgesia. During the procedure, cardiovascular and respiratory responses (blood pressure-NIBP, oxygen saturation-SatO2, respiratory rate-RR, heart rate- HR) and the Neonatal Infant Pain Scale (NIPS) were monitored.Results: There was no significant difference between the two groups (R vs C) in clinical variables and outcomes. HR changes (147+ 12 SD vs 166 + 18 SD) and NIPS (1 + 2 SD vs 5 + 2) were significantly different during the procedure, suggesting that R provided more effective analgesia than non-pharmacological measures. NIBP, RR and SatO2 were comparable, demonstrating the absence of hemodynamic and respiratory effects of R at this dosages. To maintain effective analgesia, the mean R infusion rate was 0.03 + 0.017 SD mcg/kg/min (range 0.006–0.084), albeit with a significant individual variability. The recovery time was 12 + 5 SD min. No side effects were noted.Conclusions: This study confirm the efficacy and safety of Remifentanil during PICC in premature newborn. For this procedure the mean analgesic dosage is in the recommended range.