Background: Certain antiemesis guidelines recommend combining a 5-HT₃ RA, a NK₁RA and DEX for prevention of CINV associated with highly emetogenic chemotherapy (HEC) and with anthracycline + cyclophosphamide (AC)-based MEC. The objective of this analysis was to determine if using the oral fixed-dose combination NEPA prior to initiating AC-based chemotherapy resulted in no impact on daily living (NIDL) for patients. Methods: This phase III, multinational, randomized, double-blind, double-dummy, active-controlled, parallel group trial enrolled patients with solid tumors who were naïve to cytotoxics and scheduled to initiate AC-based chemotherapy. Patients received oral NEPA (netupitant 300 mg + PALO 0.5 mg) + oral DEX 12 mg on Day 1, or oral PALO 0.5 mg + oral DEX 20 mg on Day 1. The primary efficacy endpoint was Complete Response (CR: no emesis/no rescue medication) in the delayed phase (25-120 hours after chemotherapy) in cycle 1. Secondary endpoints including NIDL for patients was assessed using the Functional Living Index—Emesis (FLIE) during the first 120 hours. Results: 1,455 patients were randomized; 1,449 were included in the efficacy analysis. Significantly more patients achieved CR during the delayed phase in the NEPA arm compared with the PALO arm (76.9% vs 69.5%, respectively: p = 0.001). Significantly more patients in the NEPA arm reported NIDL via the FLIE (78.5% vs 72.1%: p = 0.005). A greater proportion of NEPA-treated patients reported no personal hardship imposed and no daily functioning affected (75.3% vs 70.5% and 77.1% vs 71.6%, respectively, as scored by the nausea domain of the FLIE; 95.2% vs 89.2% and 95.6% vs 89.2%, respectively, as scored by the vomiting domain of the FLIE). Adverse events were similar for both groups. Conclusions: NEPA significantly improved efficacy vs PALO for prevention of CINV in AC MEC and significantly more patients experienced NIDL compared to PALO. Both regimens were generally well tolerated.