Objective Endoscopist-directed propofol (EDP) sedation is becoming more popular, with a reported safety and efficacy similar to anesthesiologist-administered propofol (AAP). The aim of this study is to compare the efficiency of EDP and AAP in patients of low-intermediate anesthetic risk. Methods A prospective cost-effectiveness comparison study was conducted. The costs of the endoscopic procedures in the EDP and AAP group were calculated using the full cost methodology after breaking down the endoscopic activity into relative value units to allocate costs in an equitable way. To determine the effectiveness, adverse events related to endoscopic sedation and the number of incomplete procedures were registered for the EDP group and compared with those published by anesthesiologists for AAP. Results: A total of 1165 and 18 919 endoscopic procedures were, respectively, included in the EDP and AAP groups. The average costs of EDP vs. AAP for gastroscopy, colonoscopy and endoscopic ultrasound were euro 182.81 vs. euro 332.93, euro 297.07 vs. euro 459.76, and euro 319.92 vs. euro 485.12, respectively. No significant differences were detected regarding the rate of overall adverse events (4.43 vs. 4.46%) or serious adverse events (0 vs. 0.17%); the rate of arterial hypotension was significantly lower in the EDP group: 0.34 vs. 1.78% [odds ratio (OR), 0.19; 95% confidence interval (CI), 0.08-0.46] and the desaturation rate was significantly lower in the AAP group: 3.26 vs. 1.29% (OR, 2.58; 95% CI, 1.85-3.60). No significant differences were found in terms of incomplete examinations (0.17 vs. 0.14%). Conclusion In patients with low-intermediate anesthetic risk referred for an endoscopic examination, EDP appears to be more efficient than AAP.