Background: Lymphedema (LE) is a known complication of breast cancer treatment. Herein we report the factors associated with LE after neoadjuvant chemotherapy (NAC) and axillary dissection (ALND) in the ACOSOG Z1071 (Alliance for Clinical Trials in Oncology) trial of patients with node-positive breast cancer. Methods: Patients who consented to the LE substudy underwent prospective arm measurements and symptom assessment after completion of NAC and at 6, 12, 18, 24, and 36 months after surgery. All patients had node-positive disease and underwent ALND after NAC. LE was defined based on symptoms of arm heaviness or swelling (LE-symptoms) or by arm volume increase of > 10% (LE-V10); severe LE was defined as volume increase > 20%. Kaplan-Meier methods were used to determine cumulative incidence. Results: 488 of 701 eligible patients consented to the LE substudy. Cumulative incidence of LE at 3 years was 37.8% (33.0-43.1%) by LE-symptoms; 58.6% (53.4-64.4%) by LE-V10; 37.2% (32.2-42.9%) for severe LE. In a univariable analysis, patient age, type of chemotherapy regimen used, breast surgical procedure, number of positive lymph nodes, and use of adjuvant radiation were not associated with risk of LE. Incidence of LE-symptoms was higher in obese patients (BMI > 30, p = 0.02) and in patients with NAC duration > 144 days (p = 0.029). Severe LE incidence was also higher with longer duration of NAC (p = 0.01). LE-V10 incidence was highest in patients with 30+ lymph nodes removed and lower when fewer lymph nodes were removed (p = 0.009). On multivariable analysis, obesity and length of NAC remained significant for LE-symptoms. Conclusions: In patients treated with NAC and ALND for node-positive breast cancer, risk of LE-symptoms increases with longer duration of neoadjuvant chemotherapy and obesity. Patients in these groups may benefit from closer surveillance for LE to allow early intervention. Support: U10CA180821, U10CA180882, UG1CA189823; Clinical trial information: NCT00881361