Background <p>5-Hydroxytryptamine 3 receptor antagonists (5-HT₃RAs) and dexamethasone are recommended to prevent azacitidine-induced nausea and vomiting. In clinical practice, 5-HT₃RAs or metoclopramide is often used without dexamethasone. In this study, we aimed to determine whether 5-HT₃RAs or metoclopramide is more effective for suppressing nausea and vomiting during azacitidine-based chemotherapy.</p> Methods <p>This study was a single-center retrospective observational study. Patients with myeloid malignancies receiving azacitidine-based regimens were treated with a 5-HT₃RA (ramosetron or granisetron, <i>n</i> = 32) or metoclopramide (<i>n</i> = 18) for preventing nausea and vomiting. The occurrence of nausea and vomiting was assessed using total control (TC), complete control (CC), and complete response (CR) rates (chi-squared test), and the time to the first emetic episode or rescue medication (Cox proportional hazard regression analysis).</p> Results <p>The 5-HT₃RA group had significantly higher rates of TC, CC, and CR than the metoclopramide group (84% vs. 22%, 91% vs. 33%, and 91% vs. 33%, respectively). The time until the first emetic episode or rescue medication was also significantly longer in the 5-HT₃RA group than in the metoclopramide group (<i>p</i> &lt; 0.001).</p> Conclusions <p>5-HT₃RAs may prevent azacitidine-induced nausea and vomiting more effectively than metoclopramide.</p> Trial registration <p>Retrospectively registered.</p>