Pseudosclerodermatous panniculitis is an unusual variant of panniculitis that results as a complication of megavoltage radiotherapy. Four women developed this unusual entity on the anterior chest and abdominal skin after receiving megavoltage therapy for either breast carcinoma or painful bone metastases from breast carcinoma. Histopathologically, the epidermis and dermis of the involved area showed little or no evidence of radiodermatitis. The main findings were confined to the subcutaneous tissue and consisted of thickened, sclerotic septa composed of both thick and thin collagen bundles, and a lobular panniculitis characterized by lipophagic granulomas and scattered lymphocytes and plasma cells. Additionally, one of the cases showed markedly dilated vascular spaces with the appearance of lymphatics in the upper part of the dermis. Pseudosclerodermatous panniculitis after irradiation is an unusual cutaneous complication of megavoltage radiotherapy that should be distinguished from subcutaneous metastatic disease, cellulitis, or connective tissue diseases involving the subcutaneous fat. The differential diagnosis can be established on the basis of the characteristic histopathologic features of postirradiation pseudosclerodermatous panniculitis.