Purpose Radiation-induced lymphopenia (RIL) correlates with poor prognoses in solid tumors. This study aimed to investigate the post-radiation therapy (RT) longitudinal lymphocyte changes and the impact of different RT techniques on RIL in breast cancer patients. Methods and Materials We prospectively assessed 607 breast cancer patients who received hypofractionated postmastectomy RT in 8 hospitals. Radiation therapy techniques included integrated photon-based intensity modulated technique (integrated RT) and a combination of photon irradiation of supraclavicular nodes and electron irradiation of the chest wall and/or the internal mammary node (hybrid RT). Peripheral lymphocyte counts (PLC) were determined before RT, weekly during RT, at 1 and 2 weeks, 3 and 6 months post-RT, and then every 6 months. The primary outcome was the nadir PLC during RT, for which associated factors were analyzed. Univariate, multivariable linear regression and propensity score matching analyses were performed to evaluate the effect of different RT techniques on nadir PLC. Results During RT, 121 (19.9%) patients had grade >= 3 RIL with a nadir PLC of 0.75 +/- 0.33 x 10(9)/L. The PLC started to recover at 1 week and reached pre-RT levels 1 year after RT and higher than pre-RT levels 2 years later. Multivariate analysis identified young age, low body mass index, radiation therapy targets involving multiple regions, integrated RT, and low pre-radiation therapy PLC as independent risk factors for nadir PLC (P < .005). The PLC at each time point during and after radiation therapy was lower in patients receiving integrated RT than in those receiving hybrid RT (P < .05). Before and after propensity score matching, integrated RT was significantly associated with lower nadir PLC after adjusting for radiation therapy targets and age (P < .001). Conclusions Breast cancer patients had prolonged lymphopenia post-RT. Integrated RT increased the risk of RIL and adversely affected recovery. Therefore, an appropriate RT technique should be considered to minimize RIL. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).