Background: The cholinergic system has attracted new interest as a pharmacological target to accomplish effective analgesia without the limitations of opioid-induced side effects. Objective: the purpose of this prospective study was a comparison between three doses of bolus and continuous infusion of epidural neostigmine versus fentanyl as an adjuvant analgesic in adults. Patients and methods: In a prospective study of 160 adult patients undergoing lower half of the body surgeries using epidural anesthesia at Zagazig University Hospitals form May 2010 to May 2013 for comparing three doses of bolus and continuous infusion of epidural neostigmine versus fentanyl as an adjuvant analgesic. Result(s): The highest neostigmine dose used in this study 200 μg bolus or 125 μg/hour infusion showed significant better pain relief parameters than lower doses regarding duration of analgesia, postoperative VAS, number of diclophenac ampoules consumed in first postoperative 24 hours and patient satisfaction score with no significant different side effects. Neostigmine showed significant lower nausea/vomiting and no pruritis with no significant difference postoperative VAS,total number of diclophenac ampoules consumed in first postoperative 24 hours and patient satisfaction score in comparison to fentanyl but fentanyl showed significant longer duration of analgesia. Conclusion(s): The highest does of neostigmine either bolus or continuous infusion is better than lower doses and fentanyl showed longer duration of analgesia with more side effects than neostigmine doses with similar postoperative VAS, number of diclophenac ampoules consumption in first postoperative 24 hours and patient satisfaction score as highest dose neostigmine either infusion or bolus.