Background <p>Infusion reactions (IRs) are common adverse events associated with HER2-targeted monoclonal antibodies, such as trastuzumab and pertuzumab. Although dexamethasone is routinely administered before docetaxel to prevent hypersensitivity, its optimal timing relative to HER2-targeted agents has not been established. This study assessed whether premedication with dexamethasone reduces the incidence of IRs associated with HER2-targeted therapy.</p> Methods <p>In this randomized, multicenter trial, 100 patients with HER2-positive early breast cancer were randomized to receive dexamethasone either before (experimental group) or after (control group) HER2-targeted agents. All patients received trastuzumab, pertuzumab, and docetaxel. The primary endpoint was the incidence of IRs during the first treatment cycle. Secondary endpoints included the incidence of grade ≥ 3 IRs, IRs in cycle 2, and overall adverse events.</p> Results <p>Incidence of IRs in cycle 1 was significantly lower in the experimental group (24.0%) than in the control group (60.0%) (<i>P</i> &lt; 0.001), corresponding to an absolute risk reduction of 36.0%. No grade ≥ 3 IRs occurred in either group. The incidence of IRs during cycle 2 was low and similar between groups (8.0% vs. 10.2%; <i>P</i> = 0.703). The incidence of treatment-related adverse events was similar between groups (98.0% vs. 100.0%, <i>P</i> &gt; 0.999). Time-course analysis revealed that most of IRs in the control group occurred before dexamethasone administration.</p> Conclusions <p>Premedication with dexamethasone before HER2-targeted therapy substantially reduced IRs without additional toxicity. This straightforward, cost-effective modification to the premedication protocol may improve tolerability in HER2-positive breast cancer and other antibody-based therapies.</p> Trial registration <p>UMIN000045181 (registered on August 18, 2021).</p>