Plasma histamine levels were obtained during palliative radiation therapy of the spine involved with systemic mastocytosis in a 68-year-old woman. Baseline plasma histamine levels were obtained before irradiation and compared to levels obtained on the third, fifth, eighth, and tenth treatment days. Despite concerns regarding histamine release with mast cell destruction following irradiation, plasma histamine levels remained within normal limits. No change in dermatologic or other systemic manifestations were observed. No untoward systemic or localized sequelae associated with mast cell degranulation in response to the administered large field of radiation was observed. Effective palliation was accomplished, and it was concluded that radiation therapy can effectively be applied in treatment of systemic mast cell disease without significant morbidity.