Based on the study of 67 affected women during a period of 15 years, we report the clinical features and natural history of focal vulvitis, a unique syndrome characterized by severe and persistent superficial dyspareunia and the presence of one to 11 (median three) minute, exquisitely tender areas of focal inflammation or ulceration on the mucosa of the vestibule. Three fourths of all lesions occur around the Bartholin gland ducts or between them posteriorly. Histopathologic study of tissues from seven patients has not shown a characteristic pattern of inflammation and fails to confirm a reported association between these lesions and the minor vestibular glands. These histologic studies and an in-depth clinical and epidemiologic investigation in nine patients, including microbiologic studies to identify infection by herpes simplex virus. Neisseria gonorrhoeae, Staphylococcus aureus, beta-hemolytic streptococci, Chlamydia trachomatis, mycoplasmas, Candida sp., trichomonads, or Mycobacterium sp., have not established an infectious etiology for this syndrome or evidence that it represents an unusual form of an autoimmune disease or Behcet's syndrome. Treatment with topical antimicrobial or corticosteroid creams, antibiotics given systemically, or cryotherapy has not been of demonstrable benefit. Approximately one half of patients eventually experience spontaneous remission but many appear to remain symptomatic indefinitely. Surgical excision of the hymenal ring and contiguous mucosa of the vestibule has brought relief and permitted resumption of sexual activity in seven of eight treated patients. While promising, operation should be reserved for patients who have experienced unremitting dyspareunia associated with the characteristic focal inflammatory lesions for at least 6 months.