Background and Aims:Neuraxial adjuants to local anesthetics is an effective technique of improving the quality and duration of postoperative analgesia. The safety and efficacy of drugs like dexmedetomidine and neostigmine as epidural medications have been sparsely investigated.Material and Methods:Combined spinal-epidural anesthesia was performed in 60 American Society of Anesthesiologists I and II patients who required lower limb surgeries of ≤3 h duration. The epidural drug was administered at the end of surgery with patients randomized into three groups. Group I, II and III received 6 ml of 0.25% bupivacaine alone, with 1 ug/kg of neostigmine and with 0.5 ug/kg of dexmedetomidine + 1 ug/kg of neostigmine, respectively. The patients were prescribed 50 mg tramadol intravenous as rescue analgesic. Patients were assessed for hemodynamic parameters, pain scores, duration of analgesia, rescue analgesic requirements and the incidence of side-effects over the next 10 h. Data was analyzed using SPSS® version 17.0 (Chicago, IL, USA). P < 0.05 was considered as statistically significant.Results:Patients in Group III had significantly longer mean duration of analgesia (273.5 min) compared to Group II (176.25 min) and Group I (144 min). There was increased requirement of fluids to maintain blood pressures in Group III. Neostigmine did not cause significant incidence of gastrointestinal side effects.Conclusions:Epidurally administered dexmedetomidine and neostigmine exhibit synergism in analgesic action. The incidence of drug-related side-effects was low in our study.