Background: Nausea control remains an unmet need for patients receiving moderately or highly emetogenic chemotherapy (MEC, HEC). The objective of this analysis was to determine the effect of the neurokinin-1 (NK-1) receptor antagonist rolapitant (VARUBI) on the prevention of nausea in patients receiving either MEC or HEC. Methods: Post hoc analyses of nausea from three randomized, double-blind, active-controlled, phase 3 clinical trials were performed for carboplatin-based MEC (n = 401), non-carboplatin-based MEC (n = 228), total MEC (n = 629), anthracycline/cyclophosphamide (AC)-based chemotherapy (n = 703), and cisplatin-based HEC (n = 1070). Patients were randomized 1:1 to oral rolapitant 180 mg or placebo ~1–2 h before chemotherapy. All patients received active control: granisetron 2 mg oral or 10 mcg/kg IV and oral dexamethasone 20 mg. Granisetron was continued on days 2 and 3 for patients receiving MEC or AC-based therapy and dexamethasone 8 mg twice daily on days 2–4 for patients receiving HEC. Patients self-assessed nausea on days 1–6 using a 100-mm visual analog scale (VAS). Percentage of patients with no nausea (NN; maximum VAS < 5 mm) or no significant nausea (NSN; maximum VAS < 25 mm) was determined for overall, delayed, and acute phases of CINV in cycle 1. Results: Rates of NN in the carboplatin-based MEC and total MEC subgroups were significantly higher (P< 0.05) with rolapitant than active control in the delayed and overall phases. In the cisplatin-based HEC subgroup, rates of NN and NSN were significantly higher (P < 0.05) with rolapitant than active control in the delayed, acute, and overall phases. Conclusions: Rolapitant prevents nausea during all CINV phases in patients receiving cisplatin-based HEC, and during the delayed and overall phases in patients receiving carboplatin-based MEC. Clinical trial information: NCT01500226, NCT01499849, NCT01500213