Introduction: Toleration of the complexity and pain of interventions such as endoscopy and colonoscopy is highly difficult for patients. Considering the disagreement on the method of injection of propofol, this study was performed to evaluate the quality of anesthesia using the three methods of propofol + fentanyl, propofol + fentanyl + lidocaine, and propofol + fentanyl + lidocaine + ketamine. Methods: This one-way blind clinical trial study included 99 patients who were admitted in three groups by block randomization method. In a group of patients that were sedated with propofol + fentanyl + lidocaine + ketamine, the dose of all drugs is reduced by half the amount of the other groups. Variables included age, sex, frequency of cough, apnea, need for jaw thrust maneuver, O 2 saturation, duration of recovery, and procedural satisfaction. Data were analyzed using SPSS version 20.0. P value of < 0.05 was considered to be significant. Results: The three groups were similar in terms of demographic characteristics. The effects of the three sedation protocols on the variables showed that patient’s apnea, cough, O 2 saturation, and also proceduralist satisfaction in the group of the patient that sedated with four drugs was significantly higher ( P < 0.05) than other groups. But there was no significant difference between the three groups when comparing the recovery time and need for jaw thrust during the procedure. Conclusion: The findings of the present study showed that the use of combination of “propofol + fentanyl + lidocaine + ketamine” with lower doses, significantly results in higher quality sedation compared with higher doses of “propofol + fentanyl + lidocaine” or “propofol + fentanyl” for scoping procedures.