ABSTRACT: PURPOSE:To report reconstructive outcomes of patients treated with post-mastectomy intensity modulated proton therapy (IMPT) following immediate breast reconstruction (IBR). MATERIALS AND METHODS:Consecutive women with breast cancer who underwent implant-based IBR and post-mastectomy IMPT were included. Clinical characteristics, dosimetry, and acute toxicity were collected prospectively and reconstruction complications retrospectively. RESULTS:Fifty-one women were treated between 2015 and 2017. Forty-two had bilateral reconstruction with unilateral IMPT. The non-irradiated contralateral breasts served as controls. Conventional fractionation (median 50?Gy/25?fractions) was administered in 37 (73%) and hypofractionation (median 40.5?Gy/15?fractions) in 14 (27%) patients. Median mean heart, ipsilateral lung V20Gy, and CTV-IMN V95% were 0.6?Gy, 13.9%, and 97.4%. Maximal acute dermatitis grade was 1 in 32 (63%), 2 in 17 (33%), and 3 in 2 (4%) patients. Surgical site infection (hazard ratio [HR] 13.19, 95% confidence interval [CI] 1.67-104.03, p?=?0.0012), and unplanned surgical intervention (HR 9.86, 95% CI 1.24-78.67, p?=?0.0068) were more common in irradiated breasts. Eight of 51 irradiated breasts and 2 of 42 non-irradiated breasts had reconstruction failure (HR 3.59, 95% CI 0.78-16.41, p?=?0.084). Among irradiated breasts, hypofractionation was significantly associated with reconstruction failure (HR 4.99, 95% CI 1.24-20.05, p?=?0.024), as was older patient age (HR 1.14, 95% CI 1.05-1.24, p?=?0.002). CONCLUSIONS:IMPT following IBR spared underlying organs and had low rates of acute toxicity. Reconstruction complications are more common in irradiated breasts, and reconstructive outcomes appear comparable with photon literature. Hypofractionation was associated with higher reconstruction failure rates. Further investigation of optimal dose-fractionation after IBR is needed.