Introduction: HTX-019 (CINVANTI®) is a novel injectable emulsion formulation of the neurokinin 1 receptor antagonist (RA) aprepitant, approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 has demonstrated a tolerable safety profile when administered via 30-min intravenous (IV) infusion and 2-min IV injection in healthy volunteers. This prospective study evaluated the safety of HTX-019 administered via 30-min IV infusion and 2-min injection (IV push) in patients with cancer. Materials and methods: This prospective single-center, randomized, safety, 2-sequence, 2-period, crossover study evaluated HTX-019 130 mg within a guideline-recommended 3-drug regimen for CINV prophylaxis in patients receiving highly (HEC) or moderately emetogenic chemotherapy (MEC). Treatment-emergent adverse events (TEAEs) were assessed at 0-30 (primary endpoint), 30-60, and >60 mins (chemotherapy administration period) following the initiation of the HTX-019 administration, focusing on infusion-site adverse events and hypersensitivity reactions (dyspnea, anaphylaxis). Results: Among 135 patients (35 MEC, 100 HEC), the most common diagnoses were ovarian (32), lung (17), endometrial (17), and colorectal (15) cancer. Patients were randomized 1:1 to a 2-min injection and a 30-min infusion of HTX-019 (sequence AB or BA), followed by a 5-hydroxytryptamine type 3 RA IV (palonosetron 0.25 mg for 30 s or ondansetron 8-16 mg for 5-10 mins), dexamethasone IV (8-12 mg for 15 mins), and the chemotherapy regimen. Both administration methods were generally well tolerated. No TEAEs occurred within 30 mins after start of HTX-019 administration. All TEAEs occurred during chemotherapy administration; 2 patients experienced 2 TEAEs following injection, and 5 experienced 8 TEAEs following infusion. Three adverse events following infusion (2 dyspnea, 1 throat closing) were considered serious. No TEAEs were considered related to HTX-019. Conclusion: Short injection of HTX-019 has a tolerable safety profile in patients with cancer, and represents an alternative method of HTX-019 administration for CINV prevention.