Background We examined the efficacy of mirtazapine in preventing delayed nausea and vomiting following highly emetogenic chemotherapy (HEC). Patients and methods Patients who had experienced delayed emesis and would be subsequently scheduled for at least three more cycles of the same chemotherapy were randomly assigned to either a mirtazapine (15 mg daily on days 2-4) or a control group. In addition, both groups received a standard triplet regimen comprising aprepitant, a 5-HT3 receptor antagonist, and dexamethasone (7.5 mg on days 2-4). The chemotherapy regimens were either an epirubicin plus cyclophosphamide regimen or cisplatin-containing regimens. The primary end point was a complete response (no emesis and no rescue treatment) to the delayed phase (25-120 h post-chemotherapy) during Cycle 1. The impact on quality of life (QOL) was assessed using the Functional Living Index-Emesis (FLIE) questionnaire. Results Of 95 enrolled patients, 46 were assigned to the mirtazapine group and 49 to the control group. The complete response rate in the delayed phase during Cycle 1 was significantly higher with mirtazapine than in the control group (78.3% versus 49.0%, P = 0.003). The main adverse effects of mirtazapine were mild to moderate somnolence and weight gain. Mean total FLIE scores were similar between the two arms. Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration: NCT02336750).