Histological changes of lichen sclerosus (LS)—a chronic inflammatory disease—are frequently found in association with squamous cell carcinoma (SCC) of the vulva, suggesting that women with this disorder are at increased risk. However, follow-up studies have been less convincing, showing that the vast majority of these patients do not go on to develop cancer. In this study, a series of 211 women affected by histologically demonstrated vulval LS were treated with topical therapy (testosterone, clobetasol) and followed prospectively by repetitive vulval examination. Three patients developed SCC of the vulva (two invasive, onein situ) at the sites affected by LS during an average follow-up period of 1 year and 8 months. Compared with the reference population, the number of cases of invasive SCC detected significantly exceeded the number estimated to occur in a comparable age-matched group. The standardized incidence rate of vulval SCC in the LS cohort was 317 (95% CI 35.7–1146.2). Cumulative risk was 14.8% (0.06% in the general female population), with a relative risk of 246.6. In conclusion, these data support the view that LS is a precursor of SCC, although characterized by slight tendency to evolve to carcinoma. Medical treatment of LS, although useful in the control of severity of disease, did not seem to be able to prevent the evolution to malignancy.