Acute radiation dermatitis commonly occurs following local radiation therapy for various cancers and, when severe, may necessitate disruption of treatment. Intense inflammatory reaction may result in a breakdown of the skin's barrier function and accompanying bacterial colonization. Bacterial superantigens may exacerbate inflammation through activation of T-cells and subsequent cytokine release. We report six cases of severe radiation dermatitis in cancer patients. Four of the six grew pathogenic bacteria, and three had psoriasiform or eczematous reactions at distant sites. Both the radiation dermatitis and the distant cutaneous reactions resolved rapidly on a combination of topical steroids and oral plus topical antibiotic therapy. We suggest that staphylococcal superinfection of acute radiodermatitis intensifies the inflammatory process and hinders repair of the epidermal barrier. Patients with acute radiation dermatitis should be investigated for secondary infection. We emphasize the importance of including topical and oral antibiotic therapy in conjunction with topical corticosteroids to eradicate infection as well as hasten repair of the skin's barrier function. These cases are presented to call attention to the role of Staphylococcus aureus in the pathogenesis of severe radiation dermatitis and the need to include appropriate antibiotic therapy based on culture in the management of acute radiation dermatitis.