Aim: To assess hematologic changes of modern prostate radiation therapy (RT) comparing different target volumes. Patients & methods: Blood samples were evaluated before (T1), during (T2–T4) and 6–8 weeks after (T5) RT in a group of 113 patients. Whole-pelvic RT up to 46 Gy was applied in 27 cases. The total dose to the prostatic fossa (n = 46)/prostate (n = 67) was 66/76 Gy. Results: Erythrocyte, leukocyte and platelet levels decreased significantly relative to baseline levels at T2–T5. Neoadjuvant hormonal therapy had an impact on hemoglobin levels before and during RT. The cumulative incidence of grade 2 leukopenia was 15 versus 2% (p = 0.02) and grade 2 anemia 8 versus 0% (p = 0.03) with versus without whole-pelvic RT, respectively. Lymphocyte decrease was larger at times T2–T5 (36 vs 3% grade 3 toxicity; p < 0.01). Conclusion: Prostate RT has a small but significant and longer effect on the blood count. Lower lymphocyte levels need to be considered when larger volumes are treated.