OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect, impairing quality of life (QoL) and increasing healthcare resource utilization. In a global phase 3 trial in patients administered moderately emetogenic chemotherapy (MEC), addition of rolapitant, a long-acting, selective neurokinin-1 receptor antagonist, to standard antiemetic therapy improved CINV control. To evaluate rolapitant outcomes in US medical practices, this post-hoc subgroup analysis assessed US patients administered MEC (n=278). METHODS: Patients were randomized 1:1 to receive a single 180-mg oral dose of rolapitant or placebo ~1-2 hours before chemotherapy on day 1; all patients received 2 mg oral granisetron plus 20 mg oral dexamethasone 30 minutes before chemotherapy on day 1 and 2 mg oral granisetron once daily on days 2 and 3. Endpoints included complete response (CR; no emesis or use of recuse medication) in the delayed (>24-120 hours), acute (≤24 hours), and overall (0-120 hours) phases post-chemotherapy. Health-related QoL was assessed using the Functional Living Index-Emesis (FLIE) questionnaire. RESULTS: The CR rate was significantly higher with rolapitant (n=139) than with control (n=139) in the delayed phase (66.2% vs 51.1% [P=0.011]), acute phase (89.2% vs 77.7% [P=0.010]), and overall phase (64.0% vs 47.5% [P=0.006]). Rolapitant significantly improved QoL versus control based on mean FLIE total scores (117.7 vs 108.1 [P<0.001]) and nausea and vomiting domain subtotal scores (56.5 vs 51.2 [P=0.002] and 61.2 vs 56.9 [P<0.001], respectively). A greater proportion of patients reported no impact of CINV on daily life (FLIE total score >108) with rolapitant versus control (84.7% vs 68.1% [P=0.003]). In the rolapitant and control groups, 86.3% and 91.4% of patients, respectively, reported ≥1 treatment-emergent adverse event. CONCLUSIONS: In US patients administered MEC, rolapitant was well tolerated and superior to control in preventing CINV and reducing the negative impact of CINV on QoL.