Backgroud <p>Gynecological day surgery patients have dual high-risk factors of both female sex and motion sickness, and the risk of postoperative nausea and vomiting (PONV) is significantly increased. This study aims to observe the effects of penehyclidine hydrochloride or droperidol combined with dexamethasone on preventing postoperative nausea and vomiting after remimazolam-alfentanil general anesthesia for gynecological day surgery.</p> Methods <p>124 patients undergoing elective gynecological day surgery were randomly divided into two groups: penehyclidine hydrochloride combined with dexamethasone group (PD group, <i>n</i>=62) and droperidol combined with dexamethasone group (DD group, <i>n</i>=62). Before anesthesia induction, PD group received intravenous injection of penehyclidine hydrochloride 0.5mg and dexamethasone 5mg, and DD group received intravenous injection of droperidol 1mg and dexamethasone 5mg. Primary outcomes: the incidence of PONV within 24h after surgery. Secondary outcomes: the incidence of PONV in PACU, the severity of PONV within 24h after surgery, sleep onset latency, recovery time, and adverse reactions.</p> Results <p>The incidence of PONV within 24h postoperatively was significantly lower in the PD group (21.3%) than in the DD group (42.6%) (<i>p</i>=0.012). Furthermore, the severity of PONV in the PD group was significantly lower than that in the DD group (<i>p</i>=0.017). There were no statistically significant differences in the remaining observation outcomes (<i>p</i> &gt;0.05).</p> Conclusion <p>Penehyclidine hydrochloride combined with dexamethasone is more effective than droperidol combined with dexamethasone in reducing the incidence and severity of PONV within 24h after remimazolam-alfentanil general anesthesia for gynecological day surgery.</p> Trial registration <p>Registered with the China Clinical Trial Registry on April 24, 2025:ChiCTR2500101387 (<a href="https://www.chictr.org.cn">https://www.chictr.org.cn</a>).</p>