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HER2-positive (HER2+) breast cancer historically exhibited the most adverse local outcomes and, consequently, has had limited representation among trials of partial breast irradiation (PBI). We hypothesized that with contemporary HER2-targeted agents, patients may now exhibit excellent disease control outcomes after adjuvant PBI. Using a prospectively maintained institutional database, we identified patients with HER2+ breast cancer treated with breast conserving surgery (BCS) and PBI from 2000 to 2022. Salient clinicopathologic and treatment parameters were collected. All patients received external beam PBI to 40 Gy in 10 daily fractions. Cumulative incidence functions were calculated to estimate the incidence of local recurrence (LR) with the competing risk of death. We identified 1248 patients who underwent PBI at our institution, of whom the study cohort comprised 52 (4%) with HER2+ breast cancer (median age, 64 years; range, 44-87). Nearly all had T1 tumors (98%; median size, 12 mm [range, 1-21 mm]). Most had estrogen receptor positive disease (88%), and all patients had negative surgical margins. Nearly all underwent sentinel node biopsy (94%), with the remainder undergoing no surgical axillary evaluation. Forty-two (81%) received chemotherapy; 40 (77%), hormone therapy; and 42 (81%), HER2-directed therapy, most commonly trastuzumab. At 143.8 person-years of follow-up (range, 7-226 months for each patient), we observed 2 LR events at 14 and 26 months, respectively, yielding a 2-year LR rate of 3.8%. No regional or distant recurrences were observed, nor were any breast-specific mortality events. Two deaths were observed, both without evidence of disease. Among a cohort of patients with HER2+ early-stage breast cancer managed with BCS and PBI, we observed a 2-year LR rate of 3.8%, with no regional or distant recurrences and excellent overall survival. These findings require confirmation with longer follow-up among larger cohorts but appear consistent with the excellent results of contemporary randomized trials of PBI unselected for HER2 status. [ABSTRACT FROM AUTHOR]