Background: Prevention of chemotherapy-induced nausea and vomiting (CINV) is vital in cancer treatment. Here, we compared the efficacy of netupitant-containing regimen; composed of NEPA, dexamethasone, and olanzapine (NEPAs), which is recommended for preventing CINV from high-emetogenic chemotherapy (HEC) to standard 3-drugs; ondansetron, dexamethasone, olanzapine for preventing CINV from high-dose cisplatin (≥75 mg/m²). Methods: This randomized, double-blind, placebo-control trial randomly assigned untreated patients who were received high-dose cisplatin in a 1:1 ratio to either NEPAs or standard 3-drugs combination regimen. Dose of dexamethasone in NEPAs regimen was modified after preplanned interim safety analysis to increase from 4 to 8 mg per day on days 2-4. The stratification factors were concurrent treatment with radiation and sex. The primary endpoint was the overall complete response (CR) rate defined as no vomiting and no use of rescue antiemetic drugs. The protocol allowed crossover to NEPAs for those who received standard 3-drugs and did not reach CR in the first cycle. We collected outcome in the first 2-cycle of treatment. Results: Between January 2019 and December 2020, hundred patients were randomly assigned to either NEPAs (n = 51) or in-house standard 3-drugs (n = 49). Demographic characteristics were well-balanced in both arms. Total events in both arms were 101 events for NEPAs and 78 events for standard 3-drug. Overall CR rate were 70% and 69% in NEPAs and standard 3-drugs, (p-value 0.87) respectively. According to emesis phase, CR in acute (0- 24 hrs.) and delay phase (24-120 hrs.) were not different in both arms; 91% vs. 89% and 72% vs. 71% in NEPAs and standard 3-drugs respectively. However, mean nausea VAS score was significantly lower in NEPAs (1.63 vs. 2.02, p-value = 0.001). The ad hoc subgroup analysis shown similar efficacy between before and after protocol amendment of NEPAs regimen in term of delay emesis CR rate; 70.9% vs. 73.9% (p-value 0.73). Conclusions: The NEPA-containing regimen did not show superiority compare to standard 3-drug in terms of complete response rate for CINV prevention among patients receiving high-dose cisplatin. Furthermore, the dexamethasone dosage of 4 vs. 8 mg per day might not affect the efficacy of delay emesis of the NEPAs regimen. Clinical trial information: TCTR20190508001.