Vulvar acanthosis with altered differentiation is an uncommon proliferation of the vulvar squamous epithelium that is typically seen in association with verrucous carcinoma, and may represent an early phase of non-HPV-related squamous neoplastic transformation. We report a case of vulvar acanthosis with altered differentiation that, over a 5-yr period, progressed first to verrucous carcinoma in association with well-differentiated invasive squamous cell carcinoma and then, after treatment with radiotherapy, to poorly differentiated carcinoma with a component of anaplastic carcinoma. This case supports the concept of vulvar acanthosis with altered differentiation as a premalignant lesion, with potential to progress to invasive carcinoma.