Background: Reduction mammoplasty (RM) at time of breast conserving surgery (BCS) is an increasingly popular procedure that reduces redundant breast folds and skin toxicity from whole breast irradiation (WBI). However, the tissue manipulation may obscure the lumpectomy cavity (LC) and hinder the ability to deliver a radiation boost to the LC, potentially impacting local control. We studied the impact of RM on acute radiation side effects and the use of LC boost. Methods: From Jan 2012 to Dec 2014, 652 consecutive women with DCIS or Stage I-III invasive cancer were treated with curative intent BCS and WBI at an urban university and 2 community practices. We reviewed the charts on an IRB-approved study with the primary endpoint of ≥ grade 3 radiation dermatitis scored via the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoint was the use of LC boost. Tested variables included age, race, body mass index, menopausal status, multi-focal disease, stage, tumor grade, receptor status, chemotherapy administered, specimen volume, 3D or intensity modulated radiation, fractionation, nodal irradiation, and planning treatment volume (PTV). Student's t-tests and Pearson's chi-square tests were utilized. Results: Forty-three (7%) of 652 patients underwent RM. Larger volumes of tissue were removed from the RM patients (median 366.5 g v 35.3 g, P= 0.0001). No grade 4 toxicities and few (2-3%) grade 3 toxicities were seen, P= 1.00. Narcotic use was similar (4-5%), P= 0.70. A LC boost was used in 476 (73%) patients; RM significantly decreased the use of a boost [16/43 (37%) v 460/609 (76%)], P= 0.0001. RM patients were more likely to have neoadjuvant chemotherapy, stage III or multi-focal disease, higher BMI, nodal irradiation, and conventional fractionation (P< 0.05). Subgroup analysis of the patients with available PTVs (67%) revealed similar volumes (P= 0.16). Conclusions: RM was associated with a decrease in the use of LC boost without significant differences in acute toxicities; however, the result is not surprising given that PTVs were similar. Further investigation is needed to better delineate LCs in patients undergoing RM to increase the use of LC boosts.