BACKGROUND: Patients with advanced myelofibrosis often suffer from symptomatic extramedullary hematopoiesis in spleen and/or liver. In case of drug-refractory disease splenomegaly is treated surgically, whereas hepatomegaly is palliated by radiotherapy (RT). CASE REPORT: A 56-year-old man with advanced and drug-refractory myelofibrosis suffered from extensive hepatomegaly with severe upper abdominal pain, satiety, weight loss, and fatigue 1.5 years after splenectomy. The patient was treated periodically with fractionated RT to the liver in order to obtain symptom control and to prevent severe symptom recurrence. RESULTS: After 2 Gy fractionated RT to a treatment field encompassing nearly the whole liver, symptoms improved and liver size decreased without severe side effects. This treatment regimen was successfully conducted 3 times in trimonthly intervals. Because symptoms recurred periodically, we then continued RT on a preemptive basis in monthly intervals and with single-dose irradiation. The patient responded well to 1 Gy preemptive single-dose RT to the liver, but not to 0.5 Gy single-dose partial liver irradiation. CONCLUSION: RT is effective in palliation of hepatomegaly in advanced myelofibrosis. Even preemptive RT can benefit selected patients with advanced disease and periodical recurrence of symptoms.