Malignant glioma patients treated with the golden standard therapy, focal radiotherapy plus concomitant daily temozolomide (radiotherapy/TMZ), often suffer severe lymphopenia. The frequency of severe lymphopenia and its predictors were analyzed by assessing adverse effects including decrease in white blood cell counts, lymphocyte counts, and neutrocyte counts according to the Common Toxicity Criteria version 3.0 (CTC) in 28 consecutive patients with pathologically verified malignant gliomas treated with radiotherapy/TMZ. Eighty-two percent of the patients suffered one or more adverse effects; lymphopenia (68%) was the most frequent adverse effect, with 32% of patients suffering CTC grade 4 lymphopenia. CTC grade 4 lymphopenia was associated with the incidence of other CTC grade 3 or 4 adverse effects and discontinuance of TMZ. Minimal lymphocyte counts during radiotherapy/TMZ and lymphocyte counts before radiotherapy/TMZ showed close linear correlation by linear regression analysis (p < 0.0001, R(2) = 0.569), and the most important predictor for CTC grade 4 lymphopenia was lymphocyte count before radiotherapy/TMZ less than 1200/microl by multivariate analysis (p < 0.0321, Exp = 13.2). Lymphocyte counts before radiotherapy/TMZ of less than 1200/microl predict severe lymphopenia during radiotherapy/TMZ.