Dystrophic epidermolysis bullosa (DEB) is a debilitating systemic disease frequently associated with biologically aggressive secondary squamous cell carcinomas arising from affected skin or mucosal surfaces. Treatment of these carcinomas with surgery, chemotherapy, or radiation is complicated by inherently poor wound healing. We report on two DEB patients treated with radiation therapy for locally advanced squamous cell carcinoma, and retrospectively analyze 10 DEB patients treated with radiation, reported in the literature. Of the 11 fully available and described case results from radiation therapy, six (54%) patients demonstrated a partial tumor response. All patients receiving > 4,500 cGy developed moist skin desquamation and delayed skin healing. Radiation therapy may be of benefit in palliating DEB patients who have locally advanced carcinoma, but has been associated with enhanced normal tissue toxicity, suggesting a narrow or absent therapeutic index between irradiated carcinoma and skin.