AimsAdequate diagnosis of human papillomavirus (HPV)‐associated high‐grade squamous intraepithelial lesion (HSIL) and HPV‐independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population‐based series of vulvar lesions, originally reported as high‐grade VIN, and assessed the cancer risk.Methods and resultsBaseline high‐grade VIN of 751 patients were categorized by histopathological reassessment, integrating the results of immunohistochemistry (p16^INK4a, p53, Ki‐67) and HPV DNA testing. Integrated analyses resulted in 88.4% HPV‐associated lesions (77.0% HSIL, 10.9% low‐grade SIL [LSIL], and 0.4% vulvar squamous cell carcinoma [VSCC]), 10.9% HPV‐independent lesions (6.1% HPV‐independent VIN, 4.7% nondysplastic lesions, and 0.1% VSCC) and 1.1% inconclusive lesions. HSIL demonstrated p16^INK4a block‐positivity in 99.0%, increased Ki‐67 in ≥2/3rd of the epithelium in 93.6%, and HPV positivity in 99.6%. In HSIL, a p53 wildtype mid‐epithelial staining pattern was common (51.6%) while this was not observed in HPV‐independent lesions. HPV‐independent VIN harboured mutant p53 patterns in 65.2% and showed a wide morphological spectrum, ranging from differentiated to nondifferentiated (‘HPV‐associated‐like’, in 41.3%). Kaplan–Meier analyses showed a 10‐year cancer risk of 8.0% in HPV‐associated HSIL, 67.4% in HPV‐independent VIN/p53mutant, and 27.8% in HPV‐independent VIN/p53wildtype. Strikingly, the 10‐year cancer risk was 73.3% in HPV‐independent VIN with nondifferentiated (‘HPV‐associated‐like’) morphology.ConclusionImmunohistochemistry by p16^INK4a and p53 is highly recommended for optimal categorization into HPV‐associated and HPV‐independent VIN, which is of utmost importance given the different cancer risk. The high cancer risk of HPV‐independent VIN underscores the need for surgical treatment and close follow‐up, especially in case of a p53 mutant pattern and/or nondifferentiated morphology.