This single-center prospective study aims to assess the outcomes and the toxicities related to the concurrent administration of trastuzumab (T) with adjuvant locoregional radiotherapy (RT) in localized breast cancer. Data of 308 patients were analyzed. T was delivered every 3 weeks (loading dose of 8 mg/kg, then 6 mg/kg) for 1 year. Left ventricular ejection fraction (LVEF), measured by echocardiography or myocardial scintigraphy, was considered as impaired when below 55%. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were carried out using the Cox model. Median follow-up was 50.2 months (13.0-126.0). Median age at diagnosis was 52 years (25-83). Internal mammary node (IMN) RT was performed in 227 patients (73.7%). After completion of RT, 26 patients (8.4%) presented an impaired LVEF: 17 (5.5%) of grade 1, 7 (2.3%) of grade 2, and 2 (0.6%) of grade 3. At 48 months, locoregional control rate was 95% [95% CI 92; 98], and overall survival rate was 98% [95% CI 96; 100]. In univariate analysis, neither the treated breast side (p = 0.655) nor IMN RT (p = 0.213) exposed patients to LVEF alteration. In multivariate analysis, clinical lymph node involvement was associated with an increased risk of locoregional and distant recurrence (p = 0.016 and p = 0.007, respectively). In this prospective study, the toxicities of concurrent T with locoregional breast RT were acceptable and the outcomes favorable. Longer follow-up is warranted to confirm these results.