Background: Post-operative nausea and vomiting (PONV) is commonly seen after modified radical mastectomy (MRM). In this randomized double-blind prospective study we compared the efficacy of ondansetron, granisetron and granisetron and dexamethasone combination for prevention of PONV following MRM in female patients. Materials and Methods: A total of 75 patients (20-60 years of age) undergoing elective MRM were randomly allocated to one of the three groups of 25 patients each. Group O received ondansetron 4 mg, Group G received granisetron 40 mcg/kg and group granisetron and dexamethasone (G + D) received granisetron 40 mcg/kg + dexamethasone 8 mg prior to induction. All episodes of PONV within 24 h after induction of anesthesia were recorded. Statistical Analysis: Statistical analysis was done using Kruskal-Wallis test (nonparametric ANOVA). Results: The incidence of complete response (no PONV, no rescue medication) was 96% with G+D, as compared with 86% with granisetron and 4% with ondansetron during 0-3h after surgery which was clinically significant (P < 0.05). Similarly clinically significant response was seen during 3-6, 6-9, 9-12 and 12-24 h of surgery. Conclusion: Granisetron and dexamethasone combination is more effective for prevention of PONV in comparison to individual ondansetron and granisetron in MRM.