BACKGROUND: Whether higher grade cervical intraepithelial neoplasia (CIN grade 2 or greater [CIN ≥ 2]) that develops because of human papillomavirus (HPV) genotypes not included in vaccines may progress to cervical cancer is largely unknown. The objectives of this study were to document expression of the cyclin-dependent kinase inhibitor 2A (p16) tumor-suppressor protein p16INK4A as a biomarker of cervical carcinogenesis or of malignant potential and to evaluate whether its expression differs between lesions associated with vaccine and nonvaccine high-risk (HR) human papillomavirus (HPV) genotypes. METHODS: The study population consisted of 371 women who had not received HPV vaccines. Women were categorized into vaccine and nonvaccine HR-HPV genotypes and lesions associated with those types. Logistic regression analyses were used to determine the association between positive expression p16INK4A and the risk of being diagnosed with CIN 2 or CIN 3. Differences in the proportion of CIN ≥2 lesions that were positive for p16INK4A expression by vaccine-related or nonvaccine-related HR-HPV genotype were determined using the Pearson chi-square test. RESULTS: Specimens that were positive for p16INK4A expression were 5.3 and 16.6 times more likely to be diagnosed as CIN 2 and CIN 3 lesions, respectively, compared to CIN 1 lesions. CIN ≥ 2 lesions that were negative for the bivalent and 9-valent HR-HPV genotypes had similar rates of positive p16INK4A expression compared with lesions that were positive for those HR-HPV genotypes. CONCLUSIONS: Lesions that may develop because of HR-HPV genotypes not included in HPV vaccines are likely to have similar malignant potential, suggesting that well developed screening programs combined with nonvaccine-based approaches may be needed to manage the residual risk of developing cervical cancer in the post-HPV vaccination era. Cancer 2016;122:3615-23. © 2016 American Cancer Society.