Herein we present the largest retrospective case-control series of deep sedation in patients with Rett syndrome, including discussion of the unique aspects of Rett syndrome that make these patients at high risk of sedation. Twenty-one patients with Rett syndrome and 21 control patients who received propofol for deep sedation to facilitate lumbar puncture were compared. Patients with Rett syndrome required significantly less propofol than control patients when standardized for weight and the duration of the procedure (P = .004). Seven of the 21 patients with Rett syndrome compared with none of the control patients experienced a serious adverse event, most of which were due to prolonged apnea, (P = .004). All adverse events were transient, and all patients returned to their baseline after the procedure was completed. Sedation of patients with Rett syndrome is associated with a relatively high rate of complications and should not be done without appropriate personnel available who recognize the risks of sedating this unique population.