Background: Down syndrome (DS) is associated with intellectual disability. DS patients may be unable to cooperate and often require general anesthesia even for minor surgeries. Rapid recovery significantly contributes to fast-tracking. This prospective randomized, double - blind study investigates the impact of desflurane and sevoflurane on recovery and early postoperative cognitive function of these patients. Methods: Forty-four patients undergoing dental surgery, were randomized to receive desflurane (DES-group) or sevoflurane (SEVO-group) for anesthesia maintenance. The primary outcome was postoperative cognitive function (Prudhoe Cognitive Function Test, PCFT) at 90 min and 4 h postoperatively. Secondary outcome measures were the time between volatile discontinuation and spontaneous breath, eye opening, extubation, orientation and response to commands, time to achieve an Aldrete score ≥ 9 in the Post-anesthesia Care Unit and time to fulfill discharge criteria (Post Anesthetic Discharge Scoring System, PADSS). Results: At 90 min, PCFT scores significantly decreased from baseline in both groups. Nevertheless, at 4 h, in DES-group there was no significant change from baseline (p = 0.163), while in SEVO-group the decrease remained significant (p < 0.001). Desflurane was also found superior regarding recovery characteristics, such as time to eye opening (p = 0.021), spatial orientation (p = 0.004), response to commands (p = 0.004). Discharge criteria were met earlier in DES-group (p = 0.018 for Aldrete score / p < 0.001 for PADSS). Conclusions: Desflurane was found superior to sevoflurane in terms of faster recovery and better preserved postoperative cognitive function in DS patients undergoing dental surgery. We suggest that desflurane, as part of a multimodal anesthetic approach, could be a useful agent to enhance early discharge from hospital of ambulatory patients with intellectual disability. Trial registration: Registered with ClinicalTrials.gov (NCT02971254, principal investigator: E.G; November 2016). [ABSTRACT FROM AUTHOR]