The aim of this study is to describe the effect of sedation and analgesia on postoperative amplitude-integrated EEG (aEEG) in newborns with congenital heart disease (CHD) undergoing heart surgery. This is a consecutive series of 26 newborns with CHD of which 16 patients underwent cardiopulmonary bypass (CPB) surgery and 10 patients did not. aEEG was monitored for at least 12 h preoperatively and started within the first 6 h postoperatively for 48 h. Outcome was assessed at 1 year of age. All 26 patients showed a normal preoperative continuous cerebral activity with sleep-wake cycles (SWC). The postoperative duration to return to normal background activity with SWC was similar for both groups. Independent of group assignment, patients requiring midazolam had a significantly later onset of a normal SWC than those without midazolam (p=0.03). Three patients in the CPB group and two in the non-CPB group showed continuous low voltage or flat trace after administration of fentanyl. These changes did not correlate with neurodevelopmental outcome. Sedation with midazolam has a transient effect on the background activity, whereas fentanyl can induce a severe pathologic background pattern. The significance of these changes on outcome is not yet clear. Thus, more attention should be paid to these effects when interpreting aEEG in this population.