A potential role of Staphylococcus aureus in bullous pemphigoid was explored by examining the colonization rate in patients with new-onset disease compared with that in age- and sex-matched controls. S.aureus colonization was observed in 85% of bullous pemphigoid lesions, 3-6-fold higher than the nares or unaffected skin from the same patients (P ≤ 0.003) and 6-fold higher than the nares or skin of controls (P ≤ 0.0015). Furthermore, 96% of the lesional isolates produced the toxic shock syndrome toxin-1 superantigen, and most of these additionally exhibited homogeneous expression of the enterotoxin gene cluster toxins. Toxic shock syndrome toxin-1‒neutralizing antibodies were not protective against colonization. However, S.aureus colonization was not observed in patients who had recently received antibiotics, and the addition of antibiotics with staphylococcal coverage eliminated S.aureus and resulted in clinical improvement. This study shows that toxic shock syndrome toxin-1‒positive S.aureus is prevalent in bullous pemphigoid lesions and suggests that early implementation of antibiotics may be of benefit. Furthermore, our results suggest that S.aureus colonization could provide a source of infection in patients with bullous pemphigoid, particularly in the setting of high-dose immunosuppression.