Aims: To determine the efficacy and safety of prophylactic ondansetron and granisetron with adjuvant dexamethasone in the prevention of PONV in patients of middle ear surgery. •     To assess the requirement of doses of rescue antiemetic in the postoperative period. •     To note the side effect of both the drugs if any Settings and Design: Prospective, randomized, single blind study. Methods and Material: After institutional review board approval and informed written consent from patients, total 100 patients were randomly assign in two groups of each 50. Group O received intravenously inj. dexamethasone 8mg two minute before induction and inj. ondansetron 4 mg diluted in 5cc NS, half hour before extubation. Group G received intravenously inj. dexamethasone 8 mg two minute before induction and inj. granisetron 1mg diluted in 5cc NS, half hour before extubation. Premedication was given to all patients. General anesthesia was given to all the patients. At the end of surgery, trachea was extubated when patient had spontaneous breathing and follow verbal command. After extubation, all the patients were shifted to post-anesthesia recovery room [PACU] and observed for post operative nausea and vomiting for 24 hours at interval of 0–2 hours, 2–6 hours, 6–12 hours,12–18 hours and 18–24 hours. Episodes of post operative nausea and vomiting were identified by spontaneous complaints by the patients. Statistical analysis used: Data were analysed by using unpaired t -test, Chi-square test. Results: Both the groups were comparable with regard to demographic data and hemodynamic parameters. The incidence of mean PONV score at different time interval was high in group O compare to group G but, the p value was more than 0.05 which was statistically not significant. The requirement of rescue antiemetic was more in group O (16%) compare to group G (6%) but, the p value was more than 0.05 which was statistically not significant. Complete response in 24 hours was more in group G (82%) compare to group O (72%) but, the p value was more than 0.05 which was statistically not significant. The incidence of PONV in 24 hours was high in group O (28%) compare to group G (18%) but, the p value was more than 0.05 which was statistically not significant. Incidence of side effects were comparable in both the groups (p value >0.05). So, in our study both the groups were comparable in prevention of PONV in middle ear surgery under general anesthesia. Conclusion: Both ondansetron and Granisetron with dexamethasone as adjuvant were equally effective and safe for prevention of post operative nausea and vomiting [PONV] in middle ear surgery. Requirement of rescue antiemetic was comparable in both the groups. Minimal side effects were observed in both the groups. So, combination of dexamethasone 8 mg with either Granisetron 1 mg or ondansetron 4 mg was equally effective and safe in prevention of post operative nausea and vomiting in middle ear surgery under general anesthesia.