Systemic mastocytosis is a rare disease characterized by mast cell infiltration of organs. Bony pain is present in up to 28% of cases and is frequently chronic and difficult to palliate. Historical attempts at pain control have exclusively involved medical therapy. We report three cases of refractory bone pain in two patients with advanced systemic mast cell disease and associated bony involvement, which were treated with radiotherapy. This report represents some of the first uses of radiotherapy in this disease. Two patients with a primary diagnosis of systemic mastocytosis and bony pain unresponsive to medical therapy were referred for palliative radiotherapy. In the first case, referral was made because of a painful thoracolumbar spine and left shoulder, and in the second, for bilateral lower extremity pain. Patients were irradiated on megavoltage equipment to 30 Gy in 200 and 300 cGy daily fractions. For the first patient, treatment reduced pain scores from 8/10 (severe) to 3-4/10 (moderate) by 1 month posttreatment, with subsequent varying pain until his death 4 months after his second treatment. The second patient achieved pain relief from 10/10 pretreatment to 1-2/10 while on treatment. This proved durable for 9 months until her death due to disease progression. The first patient had a slight exacerbation of his thrombocytopenia during his initial treatment, but otherwise neither patient experienced any acute complications from the radiation treatments. When patients with advanced systemic mastocytosis require large narcotic doses for incomplete bone pain control associated with demonstrable bony involvement, the relatively slight risks of palliative radiation to bone may be favorably weighed against the likelihood of pain relief.