Aim To clarify the incidence and risk factors of infusion-related reactions (IRRs) to trastuzumab in breast cancer patients and verify the preventive effects of glucocorticoids. Methods The electronic medical record data at the time of trastuzumab administration were retrospectively reviewed. The following exclusion criteria were applied to 229 breast cancer patients who received trastuzumab at Osaka Medical and Pharmaceutical University Hospital during the 4-year study period: missing information on human epidermal growth factor receptor type 2 (HER2) status (n=1); missing information on eosinophils (n=11); or use of treatments other than trastuzumab (n=41). Results The 176 patients included in the study received 2,320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the 2,320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone was effective in lowering IRR risk with trastuzumab (mg; per unit; odds ratio, OR=0.62; 95% confidence interval, 95% CI, 0.44‒0.86; p=0.005). Preoperative status (OR=34.7; 95% CI, 5.0–242.0; p<0.001) and high doses of trastuzumab (mg/kg; per unit; OR=59.6; 95% CI, 19.7–180.0; p<0.001) were independent risk factors for IRRs. Conclusion The results of this study suggest that premedication with dexamethasone has a protective effect against IRRs caused by trastuzumab in breast cancer treatment. Future studies are needed to determine the optimal dosing of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab treatment.