Background: Neoadjuvant chemotherapy (NAC) is commonly utilized in women with locally advanced breast cancer, usually followed by surgery and radiation therapy (RT). Many studies aimed to address the risk factors contributing to a higher incidence of lymphedema in patients with breast cancer. Our group previously reported the extent of surgery increases the risk of lymphedema. Adjuvant chemotherapy with taxane-based regimens are associated with an increased risk of lymphedema likely due an increase in interstitial extracellular fluid volume therefore resulting in fluid retention. This study aims to directly compare and characterize the risk of lymphedema in patients receiving paclitaxel versus docetaxel-based NAC. Methods: This is a retrospective study approved by our institutional review board. The study included women with breast cancer treated consecutively at our institution with taxane-based NAC followed by surgery and RT from 2006 to 2018. Patients and tumor characteristics including age, race, body mass index (BMI), clinical stage, hormone receptor, HER2 status, type of surgery, RT techniques, and type of NAC (Paclitaxel versus Docetaxel), and its association to risk of lymphedema were analyzed using univariable and multivariable binary logic regression tests. Lymphedema was assessed before RT and at follow up visits, and was identified by >2.0-cm increase in arm circumference, or >10% increase in limb volume, or new self-reported lymphedema symptoms. Results: A total of 263 patients treated with either paclitaxel or docetaxel-based NAC were identified and analyzed. At a median follow up of 28.4 months (range 3.5-158.7 months). 26.2% (69/263) of patients developed lymphedema. On a multivariable analysis, patients who underwent axillary lymph node dissection (ALND) had a significantly higher rate of lymphedema (42.6%) compared to those who had only a sentinel lymph node biopsy (SLNB, 10.5%, p<0.05). Regardless of the type of surgery, there was no significant difference in rates of lymphedema between patients who received paclitaxel versus docetaxel-based NAC (28.7% vs 21.3%). However, among high-risk patients who underwent mastectomy with ALND, NAC with Paclitaxel was associated with a significantly higher rate of lymphedema compared to docetaxel (56.8% vs 22.7%, RR 2.50, p<0.05). Conclusions: This represents one of the largest studies examining the impact of taxane-based NAC on the risk of lymphedema in women with breast cancer. In this study, paclitaxel-based NAC was associated with a significantly higher risk of lymphedema in women who underwent mastectomy and ALND compared to docetaxel based chemotherapy. A larger, balanced, prospective study is warranted to verify this previously unidentified lymphedema risk from paclitaxel and guide individualized NAC decision.