AimTo identify factors associated with baseline prolonged corrected QT (QTc) and higher risk of QTc prolongation during follow‐up in patients with Rett syndrome (RTT).MethodA retrospective review of patients receiving an electrocardiogram (ECG) between June 2012 and June 2018 was performed. Age, methyl‐CpG binding protein 2 gene (MECP2) mutation, RTT Severity Scale (RSSS) score, breathing abnormalities, seizure frequency, medications, and ECG parameters were collected. Prolonged QTc was defined as greater than or equal to 460ms. Comparisons at baseline and during follow‐up were made.ResultsIn total, 129 unique patients (all female) had 349 ECGs. At baseline, 12 (9.3%) had a prolonged QTc (median 474ms, interquartile range 470–486ms) and were more likely to have moderate/severe breathing abnormalities (66.7% vs 24.8%; p=0.005) and take selective serotonin reuptake inhibitors (SSRIs) (41.7% vs 15.4%; p=0.04). There was no difference in age, RSSS score, seizures, or mutation. Twenty‐six developed prolonged QTc during a median follow‐up of 1 year 7 months (interquartile range 0–3y 6mo). QTc prolongation was associated with p.(Thr158Met) mutation versus the remaining six common mutations (hazard ratio 4.1, 95% confidence interval 1.4–12.0; p=0.01) but not with age, RSSS score, seizures, breathing abnormalities, or SSRIs.InterpretationBreathing abnormalities and SSRIs were associated with baseline QTc prolongation and those with p.(Thr158Met) mutation were more likely to develop prolonged QTc over time. Identification of patients with prolonged QTc warrants increased clinical monitoring.What this paper adds Breathing abnormalities and selective serotonin reuptake inhibitors are associated with prolonged baseline corrected QT (QTc). Development of QTc prolongation is associated with the p.(Thr158Met) mutation.