This prospective case study documents the development of invasive squamous cell carcinoma (SCC) almost 40 months after initial diagnosis and treatment by wide local excision of squamous vulvar intraepithelial neoplasia (VIN) of simplex (or differentiated) type. A 52-year-old woman had no history of a prior or synchronous SCC, nor did she have lichen sclerosus. Simplex VIN involved the margin of the excision specimen, leading to local recurrences and progression into invasive SCC of the conventional keratinizing type. This study conclusively demonstrates that simplex VIN is a distinct type of squamous intraepithelial carcinoma (ie, carcinoma in situ) and a direct precursor of keratinizing SCC.