Purpose <p>This study examined the feasibility of a steroid-sparing approach in a dose-dense AC regimen in breast cancer patients, while integrating olanzapine to manage chemotherapy-induced nausea and vomiting (CINV).</p> Methods <p>A prospective, single-center study was conducted with 30 patients diagnosed with Stage I–III breast cancer who underwent treatment with a dose-dense AC regimen. Patients were given prophylactic olanzapine from days 1 to 4 along with the standard three-drug combination antiemetic regimen, excluding dexamethasone on days 2 and 3. Nausea, vomiting, and drowsiness were evaluated using a validated 4-point Likert scale. The main outcome measured was the complete response (CR) rate in the delayed phase.</p> Results <p>The CR rates were 73% and 63% in the acute and delayed phases, respectively. The total control and complete control rates in the acute phase were 60% and 73%, respectively, while in the delayed phase, they were 36.6% and 63%. Moderate-to-severe daytime sleepiness was observed in 40% of the patients. The mean nausea score on the EORTC QLQ-C30 remained within the minimally important difference threshold for all four treatment cycles.</p> Conclusion <p>This study suggests that olanzapine may enable steroid reduction without compromising CINV control in patients receiving dose-dense AC. A steroid-sparing regimen could mitigate steroid-related adverse effects while maintaining antiemetic efficacy. Further large-scale studies are warranted to validate these findings and optimize steroid-sparing strategies in antiemetic protocols.</p> Trial registration <p>This study was registered on August 29, 2020, in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000041605).</p>