Post Operative Induced Nausea and Vomiting (PONV) is a side effect of nausea and vomiting felt by patients after surgery, which is very disturbing. Approximately 46% to 70% of patients who do not receive antiemetic therapy will feel nausea and vomiting after laparoscopic cholecystectomy surgery. This can affect the costs to be paid by the patient. To prevent PONV, patients can be given prophylactic medication for nausea and vomiting. Ondansetron and a combination of Ondansetron and Dexamethasone are often used as a prophylactic nausea and vomiting drugs. The purpose of this study was to determine cost effectiveness between the combination of Ondansetron and Dexamethasone and single Ondansetron as PONV prophylactic therapy after Cholecystectomy surgery. This study was an observational study with a cross sectional study design. Data collected in February 2019 retrospectively by looking medical record of patients who had Cholecystectomy surgery for the period of January 2017 to August 2018 at Bethesda Hospital Yogyakarta. The total population was 165 patients and the sample including criteria were 54 patients. The Analysis method to analyze the effectiveness of the drug use the Chi-Square statistical test method and to analyze the cost of drugs used the independent t-test statistical method. The results showed that in the Ondansetron group there was no incidence of nausea vomiting, but in the combination Ondansetron and Dexamethasone group there were 2 incidents of nausea and vomiting. After being tested statistically there was no significant difference between the effectiveness of the combination of Ondansetron and Dexamethasone and single Ondansetron as PONV prophylaxis with a p value > 0.05. The results of the cost analysis between the combination of Ondansetron and Dexamethasone and single Ondansetron showed a significant difference with the p value <0.05. The conclusion of this study is that there are no significant difference between the effectiveness of the combination of Ondansetron and Dexamethasone and single Ondansetron as PONV prophylactic therapy after Cholecystectomy surgery. But there are significant differences between the costs incurred by patients for the use of PONV prophylactic drugs, patients using a combination of Ondansetron and Dexamethasone incurred more costs than patients using single Ondansetron as PONV prophylaxis after Cholecystectomy surgery.