Background: One of the most troublesome complications after middle-ear surgeries has been postoperative nausea and vomiting (PONV). A notable decrease in PONV has been observed with the use of 5-hydroxytryptamine type 3 receptor antagonists and glucocorticoids. Aim: This study aimed to evaluate the effectiveness of the combination of intravenous methylprednisolone and ondansetron with ramosetron alone in preventing PONV in patients undergoing middle-ear surgeries. Settings and Design: This was a prospective, randomized, double-blind study that comprised sixty patients in the age group of 18–60 years belonging to the American Society of Anesthesiologists (ASA) physical status classification I or II and undergoing middle-ear surgery. Materials and Methods: With the help of computer-generated randomization table, sixty patients in the age group of 18–60 years belonging to ASA physical status classification I or II and undergoing middle-ear surgery were randomly allotted to receive a combination of methylprednisolone 40 mg (given at the beginning of surgery) and ondansetron 4 mg (given near the end of surgery) (Group MO, n = 30) or ramosetron 0.3 mg (near the end of surgery) (Group R, n = 30). In both the groups, the incidence of PONV was studied. Statistical Analysis: Chi-square test or Fisher's exact test was utilized to analogize the categorical variables. Independent t-test was utilized to analogize the continuous variables. Results: In the first 2 h after the surgery, the difference between the two groups regarding the incidence of PONV was insignificant. Between 2 h and 24 h, the incidence of nausea was lowered significantly in the group MO compared to the group R (P = 0.01). Between 24 h and 48 h, the incidence of nausea was more in group R compared to the combination therapy group, which was statistically significant. Conclusion: The combination therapy is better than ramosetron alone for the prevention of PONV after middle-ear surgery. Therefore, we advocate a combination of methylprednisolone and ondansetron for prophylaxis for PONV in middle-ear surgeries. [ABSTRACT FROM AUTHOR]