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Introduction: Chemotherapy-induced nausea and vomiting (CINV) is one of the adverse events that most affects oncologic patients' quality of life. Carboplatin AUC ≥ 4 belongs to agents with high emetic risk (moderate risk in ASCO guidelines). We aimed to compare the effectiveness of netupitant/palonosetron and dexamethasone triple combination (TC) therapy versus ondansetron and dexamethasone double combination (DC) therapy as antiemetic prophylaxis in patients with carboplatin AUC ≥ 4. As a secondary endpoint, in TC group we evaluated the effectiveness of changing NEPA administration timing from 1 h to 15 min before chemotherapy., Methods: Open-label prospective study conducted in a tertiary-care hospital in patients receiving carboplatin AUC ≥ 4. CINV was evaluated using MASCC antiemetic tool, in acute (<24 h) and delayed phase (24-120 h). Results were analyzed using χ 2 test., Results: Two-hundred four completed questionnaires (CQ) were analyzed (76 in DC and 128 in TC). The proportion of patients who remained emesis-free was superior for TC-treated group compared to DC, either in acute (99.2% vs 92.1%, p  = 0.0115) and delayed phase (97.6% vs 90.7%, p  = 0.043). Likewise, a higher proportion of TC-treated patients compared to DC remained nausea-free for the first 24 h after treatment (90.6% vs 71%, p  = 0.0004) and between 24 and 120 h (82.3% vs 62.7%, p  = 0.0025). The change of NEPA administration time showed similar effectiveness in terms of CINV control (81.6% vs 74.5%, p  = 0.70)., Conclusions: TC showed superiority in early and delayed CINV control in carboplatin AUC ≥ 4 regimens, with no significant differences among cancer types. Change in NEPA administration timing has beneficial implications; it allows NEPA to be administered at hospitals before chemotherapy session., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.