Background: Fosnetupitant (FN) is a phosphorylated pro-drug of netupitant that has high binding affinity and selectivity for the neurokinin 1 receptor and a long half-life of 70 h. Recent studies have reported that fosaprepitant (FA) has a risk for developing injection site reactions (ISRs) in patients with breast cancer who receive doxorubicin-cyclophosphamide/epirubicin-cyclophosphamide (AC/EC)-based treatments. Previous studies have shown that FN may have a low risk of ISRs and could potentially address this unmet medical need. The present study (JapicCTI-194691) was intended to evaluate the safety profile, including ISRs, of FN in patients receiving AC/EC treatment. For exploratory purposes, we set the FA group as the exploratory arm. A separate pivotal phase 3 study (JapicCTI-194611) was conducted to verify the efficacy and safety of FN compared with FA in patients receiving cisplatin-based chemotherapy. Methods: Patients scheduled to receive AC/EC were randomly assigned 1:1 to receive FN 235 mg or FA 150 mg in a double-blind manner, in combination with intravenous palonosetron (PALO) 0.75 mg and dexamethasone (DEX) 9.9 mg on day 1. The stratification factors were age class ( < 55 years vs. ≥55 years) and site. The primary endpoint was the incidence of treatment-related adverse events (TRAEs) of FN. In addition, the ISRs were investigated as secondary endpoints. Efficacy outcomes were also evaluated as secondary endpoint. Results: Between April 2019 and March 2020, total 102 patients were enrolled in the study. Fifty-two patients were randomized to the FN group and 50 to the FA group, and all of them were treated with the study drug and evaluated for safety. The baseline characteristics were generally balanced, except for the history of motion sickness (54.9% vs. 44.9%) and non-smokers (78.4% vs. 63.3%) in the FN and FA groups, respectively, which are considered as risk factors for chemotherapy-induced nausea and vomiting. The primary endpoint, the incidence of TRAEs was 21.2% (n = 11) (95% CI 11.1% – 34.7%) in the FN group, which was similar to that in the FA group [22.0% (n = 11) (95% CI 11.5% - 36.0%) ]. Any cause or treatment-related ISRs were observed in 5.8% (n = 3) and 0% (n = 0), respectively, in the FN group and 26.0% (n = 13) and 10.0% (n = 5), respectively, in the FA group. The overall (0–120 h) complete response (no emetic event and no rescue medication) rate standardized by age category was 45.9% (n = 23) in the FN group and 51.3% (n = 25) in the FA group. Conclusions: The safety of FN in combination with PALO and DEX was favorable. Risk of ISR by FN was quite low in the AC/EC setting. Clinical trial information: JapicCTI-194691.