Background The SEDASYS System is an investigational computer-assisted personalized sedation system integrating propofol delivery with patient monitoring to enable endoscopist/nurse teams to safely administer propofol. Objective To compare the safety and effectiveness of the SEDASYS System to the current standard of care for sedation during routine endoscopic procedures. Design Nonblinded multicenter randomized comparative study. Setting Four ambulatory surgery centers, 3 endoscopy centers, and 1 academic center in the United States. Patients One thousand American Society of Anesthesiologists physical status class I to III adults undergoing routine colonoscopy or EGD. Interventions Sedation with the SEDASYS System (SED) and sedation with each site's current standard of care (CSC; benzodiazepine/opioid combination). Main Outcome Measurements Area under the curve of oxygen desaturation was the primary endpoint. Secondary endpoints included patient satisfaction, clinician satisfaction, level of sedation, and patient recovery time. Results Four hundred ninety-six patients were randomized to SED and 504 to CSC. Area under the curve of oxygen desaturation was significantly lower for SED (23.6 s·%) than for CSC (88.0 s·%; P = .028). Patients were predominately minimally to moderately sedated in both groups. SED patients were significantly more satisfied than CSC patients ( P = .007). Clinician satisfaction was greater with SED than with CSC ( P < .001). SED patients recovered faster than CSC patients ( P < .001). The incidence of adverse events was 5.8% in the SED group and 8.7% in the CSC group. Limitations Nonblinded. Conclusions The SEDASYS System could provide endoscopist/nurse teams a safe and effective on-label means to administer propofol to effect minimal to moderate sedation during routine colonoscopy and EGD. ( ClinicalTrials.gov identifier: NCT00452426 .)