The natural history of vaginal intraepithelial neoplasia (VAIN) was studied in 23 patients followed for at least 3 years with no treatment. The mean age of the patients was 41 years of age. A large proportion of the VAIN lesions (50%) were multifocal, and approximately one half of the lesions were associated with concomitant cervical or vulvar intraepithelial neoplasia. Progression to invasive vaginal carcinoma occurred in two (9%) cases, persistence of VAIN occurred in three (13%) cases, and regression of VAIN occurred in 18 (78%) cases. The risk for progression to invasive carcinoma emphasizes the significance of colposcopic examination of the vagina with directed biopsy specimens obtained from all lesions.