PURPOSE/OBJECTIVE: Lymphedema after breast cancer treatment can be an irreversible condition with a negative impact on quality of life. The goal of this study was to identify radiation therapy-related risk factors for lymphedema. METHODS AND MATERIALS: From 2005 to 2012, we prospectively performed arm volume measurements on 1476 breast cancer patients at our institution using a Perometer. Treating each breast individually, 1099 of 1501 patients (73%) received radiation therapy. Arm measurements were performed preoperatively and postoperatively. Lymphedema was defined as ≥10% arm volume increase occurring >3 months postoperatively. Univariate and multivariate Cox proportional hazard models were used to evaluate risk factors for lymphedema. RESULTS: At a median follow-up time of 25.4 months (range, 3.4-82.6 months), the 2-year cumulative incidence of lymphedema was 6.8%. Cumulative incidence by radiation therapy type was as follows: 3.0% no radiation therapy, 3.1% breast or chest wall alone, 21.9% supraclavicular (SC), and 21.1% SC and posterior axillary boost (PAB). On multivariate analysis, the hazard ratio for regional lymph node radiation (RLNR) (SC ± PAB) was 1.7 (P=.025) compared with breast/chest wall radiation alone. There was no difference in lymphedema risk between SC and SC + PAB (P=.96). Other independent risk factors included early postoperative swelling (P<.0001), higher body mass index (P<.0001), greater number of lymph nodes dissected (P=.018), and axillary lymph node dissection (P=.0001). CONCLUSIONS: In a large cohort of breast cancer patients prospectively screened for lymphedema, RLNR significantly increased the risk of lymphedema compared with breast/chest wall radiation alone. When considering use of RLNR, clinicians should weigh the potential benefit of RLNR for control of disease against the increased risk of lymphedema.