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Over the recent years, awareness for lymphopenia as toxicity of radiotherapy is increased. Lymphopenia is reported in patients treated with chemoradiotherapy for several cancer types. In esophageal cancer the incidence of grade IV lymphopenia ranges from 11 to 40%. Grade IV lymphopenia is associated with worse overall survival and a lower incidence of pathologic complete response after treatment. The risk of lymphopenia is predicted by baseline absolute lymphocyte count, planning target volume (PTV), age, body mass index and radiotherapy technique (proton vs photon radiotherapy). Others report on associations between radiation dose to critical organs like heart, spleen, bone marrow, or the circulation blood pool and the development of lymphopenia. New radiotherapy techniques, that aim to reduce the dose to organs at risk, might consequently reduce the risk of lymphopenia. In the treatment of esophageal cancer, proton radiotherapy, with dose reductions to heart and lungs, reduces the risk of grade IV lymphopenia compared to photon radiotherapy (IMRT). In summary, lymphopenia is a frequently observed side effect of chemoradiotherapy in several tumour sites. Radiotherapy techniques that reduce the dose to critical organs, like proton radiotherapy, seem to reduce the risk of lymphopenia.